Biology of the cell cycle inhibitor p21CDKN1A: molecular mechanisms and relevance in chemical toxicology
详细信息 查看全文
- 作者：Ilaria Dutto (1)
Micol Tillhon (1)
Ornella Cazzalini (2)
Lucia A. Stivala (2)
Ennio Prosperi (1)
1. Genome Stability Group ; Institute of Molecular Genetics ; National Research Council (CNR) ; Via Abbiategrasso 207 ; 27100 ; Pavia ; Italy
2. General Pathology and Immunology Unit ; Department of Molecular Medicine ; University of Pavia ; Via Ferrata 9 ; 27100 ; Pavia ; Italy - 关键词：p21CDKN1A/WAF1/CIP1 ; Cell cycle inhibition ; DNA damage response ; DNA repair ; Genotoxic compounds ; Chemical toxicity
- 刊名：Archives of Toxicology
- 出版年：2015
- 出版时间：February 2015
- 年：2015
- 卷：89
- 期：2
- 页码：155-178
- 全文大小：815 KB
- 参考文献：1. Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9(6):400鈥?14. doi:10.1038/nrc2657
2. Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A (2008) PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev 22(18):2496鈥?506. doi:10.1101/gad.1676108
3. Abbas I, Gar莽on G, Saint-Georges F, Billet S, Verdin A, Gosset P, Mulliez P, Shirali P (2010) Occurrence of molecular abnormalities of cell cycle in L132 cells after in vitro short-term exposure to air pollution PM(2.5). Chem Biol Interact 188(3):558鈥?65. doi:10.1016/j.cbi.2010.09.014
4. Abella N, Brun S, Calvo M, Tapia O, Weber JD, Berciano MT, Lafarga M, Bachs O, Agell N (2010) Nucleolar disruption ensures nuclear accumulation of p21 upon DNA damage. Traffic 6:743鈥?55. doi:10.1111/j.1600-0854.2010.01063.x
5. Adler M, M眉ller K, Rached E, Dekant W, Mally A (2009) Modulation of key regulators of mitosis linked to chromosomal instability is an early event in ochratoxin A carcinogenicity. Carcinogenesis 30(4):711鈥?19. doi:10.1093/carcin/bgp049
6. Agarwal C, Singh RP, Dhanalakshmi S, Tyagi AK, Tecklenburg M, Sclafani RA, Agarwal R (2003) Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene 22(51):8271鈥?282. doi:10.1038/sj.onc.1207158
7. Aimola P, Carmignani M, Volpe AR, Di Benedetto A, Claudio L, Waalkes MP, van Bokhoven A, Tokar EJ, Claudio PP (2012) Cadmium induces p53-dependent apoptosis in human prostate epithelial cells. PLoS ONE 7(3):e33647. doi:10.1371/journal.pone.0033647
8. Amador V, Ge S, Santamar铆a PG, Guardavaccaro D, Pagano M (2007) APC/C(Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase. Mol Cell 27(3):462鈥?73. doi:10.1016/j.molcel.2007.06.013
9. Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K, Mizutani S (1999) Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO J 18(5):1223鈥?234. doi:10.1093/emboj/18.5.1223
10. Avkin S, Sevilya Z, Toube L, Geacintov N, Chaney SG, Oren M, Livneh Z (2006) p53 and p21 regulate error-prone DNA repair to yield a lower mutation load. Mol Cell 22(3):407鈥?13. doi:10.1016/j.molcel.2006.03.022
11. Bach A, Bender-Sigel J, Schrenk D, Fl眉gel D, Kietzmann T (2010) The antioxidant quercetin inhibits cellular proliferation via HIF-1-dependent induction of p21WAF. Antioxid Redox Signal 13(4):437鈥?48. doi:10.1089/ars.2009.3000
12. Badie C, Dziwura S, Raffy C, Tsigani T, Alsbeih G, Moody J, Finnon P, Levine E, Scott D, Bouffler S (2008) Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment. Br J Cancer 98(11):1845鈥?851. doi:10.1038/sj.bjc.6604381
13. Baldi A, Groeger AM, Esposito V, Cassandro R, Tonini G, Battista T, Di Marino MP, Vincenzi B, Santini M, Angelini A, Rossiello R, Baldi F, Paggi MG (2002) Expression of p21 in SV40 large T antigen positive human pleural mesothelioma: relationship with survival. Thorax 57(4):353鈥?56
14. Baptiste-Okoh N, Barsotti AM, Prives C (2008) Caspase 2 is both required for p53-mediated apoptosis and downregulated by p53 in a p21-dependent manner. Cell Cycle 7(9):1133鈥?138
15. Battelli C, Nikopoulos GN, Mitchell JG, Verdi JM (2006) The RNA-binding protein Musashi-1 regulates neural development through the translational repression of p21WAF-1. Mol Cell Neurosci 31(1):85鈥?6. doi:10.1016/j.mcn.2005.09.003
16. Bayram H, Ito K, Issa R, Ito M, Sukkar M, Chung KF (2006) Regulation of human lung epithelial cell numbers by diesel exhaust particles. Eur Respir J 27(4):705鈥?13. doi:10.1183/09031936.06.00012805
17. Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E (2010) Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proc Natl Acad Sci USA 107(13):5845鈥?850. doi:10.1073/pnas.1000830107
18. Bezine E, Vignard J, Mirey G (2014) The cytolethal distending toxin effects on Mammalian cells: a DNA damage perspective. Cells 3(2):592鈥?15. doi:10.3390/cells3020592
19. Blagosklonny MV (2002) Are p27 and p21 cytoplasmic oncoproteins? Cell Cycle 1(6):391鈥?93
20. Blagus T, Zager V, Cemazar M, Sersa G, Kamensek U, Zegura B, Nunic J, Filipic M (2014) A cell-based biosensor system HepG2CDKN1A-DsRed for rapid and simple detection of genotoxic agents. Biosens Bioelectron 61:102鈥?11. doi:10.1016/j.bios.2014.05.002
21. Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M (2003) Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation. Cell 115(1):71鈥?2
22. Bondarenko O, Juganson K, Ivask A, Kasemets K, Mortimer M, Kahru A (2013) Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: a critical review. Arch Toxicol 87(7):1181鈥?200. doi:10.1007/s00204-013-1079-4
23. Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A (2003) Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 278(28):25752鈥?5757. doi:10.1074/jbc.M301774200
24. Bose R, Onishchenko N, Edoff K, Janson Lang AM, Ceccatelli S (2012) Inherited effects of low-dose exposure to methylmercury in neural stem cells. Toxicol Sci 130(2):383鈥?90. doi:10.1093/toxsci/kfs257
25. Brosh R, Assia-Alroy Y, Molchadsky A, Bornstein C, Dekel E, Madar S, Shetzer Y, Rivlin N, Goldfinger N, Sarig R, Rotter V (2013) p53 counteracts reprogramming by inhibiting mesenchymal-to-epithelial transition. Cell Death Differ 20(2):312鈥?20. doi:10.1038/cdd.2012.125
26. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377(6549):552鈥?57
27. Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA (1999) Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. Proc Natl Acad Sci USA 96(3):1002鈥?007
28. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW, Vogelstein B (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282(5393):1497鈥?501
29. Cao F, Zhou T, Simpson D, Zhou Y, Boyer J, Chen B, Jin T, Cordeiro-Stone M, Kaufmann W (2007) p53-Dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts. Toxicol Appl Pharmacol 218(2):174鈥?85. doi:10.1016/j.taap.2006.10.031
30. Casini T, Pelicci PG (1999) A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest. Oncogene 18(21):3235鈥?243. doi:10.1038/sj.onc.1202630
31. Cazzalini O, Perucca P, Riva F, Stivala LA, Bianchi L, Vannini V, Ducommun B, Prosperi E (2003) p21CDKN1A does not interfere with loading of PCNA at DNA replication sites, but inhibits subsequent binding of DNA polymerase delta at the G1/S phase transition. Cell Cycle 2(6):596鈥?03.聽doi:10.4161/cc.2.6.502
32. Cazzalini O, Perucca P, Savio M, Necchi D, Bianchi L, Stivala LA, Ducommun B, Scovassi AI, Prosperi E (2008) Interaction of p21(CDKN1A) with PCNA regulates the histone acetyltransferase activity of p300 in nucleotide excision repair. Nucleic Acids Res 36(5):1713鈥?722. doi:10.1093/nar/gkn014
33. Cazzalini O, Don脿 F, Savio M, Tillhon M, Maccario C, Perucca P, Stivala LA, Scovassi AI, Prosperi E (2010a) p21CDKN1A participates in base excision repair by regulating the activity of poly(ADP-ribose) polymerase-1. DNA Repair (Amst) 9(6):627鈥?35. doi:10.1016/j.dnarep.2010.02.011
34. Cazzalini O, Scovassi AI, Savio M, Stivala LA, Prosperi E (2010b) Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat Res 704(1鈥?):12鈥?0. doi:10.1016/j.mrrev.2010.01.009
35. Cazzalini O, Perucca P, Mocchi R, Sommatis S, Prosperi E, Stivala LA (2014a) DDB2 association with PCNA is required for its degradation after UV-induced DNA damage. Cell Cycle 13(2):240鈥?48. doi:10.4161/cc.26987
36. Cazzalini O, Sommatis S, Tillhon M, Dutto I, Bachi A, Rapp A, Nardo T, Scovassi AI, Necchi D, Cardoso MC, Stivala LA, Prosperi E (2014b) CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis. Nucleic Acids Res 42(13):8433鈥?448. doi:10.1093/nar/gku533
37. Chang BD, Watanabe K, Broude EV, Fang J, Poole JC, Kalinichenko TV, Roninson IB (2000) Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci USA 97(8):4291鈥?296
38. Chang CH, Yu FY, Wu TS, Wang LT, Liu BH (2011) Mycotoxin citrinin induced cell cycle G2/M arrest and numerical chromosomal aberration associated with disruption of microtubule formation in human cells. Toxicol Sci 119(1):84鈥?2. doi:10.1093/toxsci/kfq309
39. Chang X, Lu W, Dou T, Wang X, Lou D, Sun X, Zhou Z (2013) Paraquat inhibits cell viability via enhanced oxidative stress and apoptosis in human neural progenitor cells. Chem Biol Interact 206(2):248鈥?55. doi:10.1016/j.cbi.2013.09.010
40. Charrier-Savournin FB, Ch芒teau MT, Gire V, Sedivy J, Piette J, Dulic V (2004) p21-Mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress. Mol Biol Cell 15(9):3965鈥?976. doi:10.1091/mbc.E03-12-0871
41. Chatterjee D, Bhattacharjee P, Sau TJ, Das JK, Sarma N, Bandyopadhyay AK, Roy SS, Giri AK (2014) Arsenic exposure through drinking water leads to senescence and alteration of telomere length in humans: A case-control study in West Bengal, India. Mol Carcinog. doi:10.1002/mc.22150
42. Chen J, Saha P, Kornbluth S, Dynlacht BD, Dutta A (1996) Cyclin-binding motifs are essential for the function of p21CIP1. Mol Cell Biol 16(9):4673鈥?682
43. Chen X, Chi Y, Bloecher A, Aebersold R, Clurman BE, Roberts JM (2004) N-acetylation and ubiquitin-independent proteasomal degradation of p21(Cip1). Mol Cell 16(5):839鈥?47. doi:10.1016/j.molcel.2004.11.011
44. Chen LC, Liu YC, Liang YC, Ho YS, Lee WS (2009) Magnolol inhibits human glioblastoma cell proliferation through upregulation of p21/Cip1. J Agric Food Chem 57(16):7331鈥?337. doi:10.1021/jf901477g
45. Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT (2000) Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287(5459):1804鈥?808
46. Chiappara G, Gjomarkaj M, Virz矛 A, Sciarrino S, Ferraro M, Bruno A, Montalbano AM, Vitulo P, Minervini MI, Pipitone L (2013) Pace E (2013) The role of p21 Waf1/Cip1 in large airway epithelium in smokers with and without COPD. Biochim Biophys Acta 1832(10):1473鈥?481. doi:10.1016/j.bbadis.2013.04.022
47. Chiappara G, Gjomarkaj M, Sciarrino S, Vitulo P, Pipitone L, Pace E (2014) Altered expression of p21, activated caspase-3, and PCNA in bronchiolar epithelium of smokers with and without chronic obstructive pulmonary disease. Exp Lung Res 40(7):343鈥?53. doi:10.3109/01902148.2014.928836
48. Child ES, Mann DJ (2006) The intricacies of p21 phosphorylation: protein/protein interactions, subcellular localization and stability. Cell Cycle 5(12):1313鈥?319
49. Chinni SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH (2001) Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 20(23):2927鈥?936. doi:10.1038/sj.onc.1204365
50. Cho SJ, Kang NS, Park SY, Kim BO, Rhee DK, Pyo S (2003) Induction of apoptosis and expression of apoptosis related genes in human epithelial carcinoma cells by Helicobacter pylori VacA toxin. Toxicon 42(6):601鈥?11
51. Choi YJ, Yin HQ, Suh HR, Lee YJ, Park SR, Lee BH (2011) Involvement of E2F1 transcriptional activity in cadmium-induced cell-cycle arrest at G1 in human lung fibroblasts. Environ Mol Mutagen 52(2):145鈥?52. doi:10.1002/em.20593
52. Chopin V, Toillon RA, Jouy N, Le Bourhis X (2004) P21(WAF1/CIP1) is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF-7 breast cancer cells. Oncogene 23(1):21鈥?9. doi:10.1038/sj.onc.1207020
53. Cmielov谩 J, Rez谩膷ov谩 M (2011) p21Cip1/Waf1 protein and its function based on a subcellular localization [corrected]. J Cell Biochem 112(12):3502鈥?506. doi:10.1002/jcb.23296
54. Coates SS, Lehnert BE, Sharma S, Kindell SM, Gary RK (2007) Beryllium induces premature senescence in human fibroblasts. J Pharmacol Exp Ther 322(1):70鈥?9
55. Coqueret O (2003) New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 13(2):65鈥?0.聽doi:10.1016/S0962-8924(02)00043-0
56. Coqueret O, Gascan H (2000) Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1. J Biol Chem 275(25):18794鈥?8800. doi:10.1074/jbc.M001601200
57. Cortes-Bratti X, Karlsson C, Lagerg氓rd T, Thelestam M, Frisan T (2001) The Haemophilus ducreyi cytolethal distending toxin induces cell cycle arrest and apoptosis via the DNA damage checkpoint pathways. J Biol Chem 276(7):5296鈥?302. doi:10.1074/jbc.M008527200
58. Creton S, Zhu H, Gooderham NJ (2005) A mechanistic basis for the role of cycle arrest in the genetic toxicology of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Toxicol Sci 84(2):335鈥?43. doi:10.1093/toxsci/kfi075
59. Delavaine L, La Thangue NB (1999) Control of E2F activity by p21Waf1/Cip1. Oncogene 18(39):5381鈥?392. doi:10.1038/sj.onc.1202923
60. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P (1995) Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82(4):675鈥?84
61. Devgan V, Mammucari C, Millar SE, Brisken C, Dotto GP (2005) p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev 19(12):1485鈥?495. doi:10.1101/gad.341405
62. Di Cunto F, Topley G, Calautti E, Hsiao J, Ong L, Seth PK, Dotto GP (1998) Inhibitory function of p21Cip1/WAF1 in differentiation of primary mouse keratinocytes independent of cell cycle control. Science 280(5366):1069鈥?072
63. Dotto GP (2000) p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta 1471(1):M43鈥揗56.聽doi:10.1016/S0304-419X(00)00019-6
64. Duensing A, Ghanem L, Steinman RA, Liu Y, Duensing S (2006) p21(Waf1/Cip1) deficiency stimulates centriole overduplication. Cell Cycle 5(24):2899鈥?902
65. Duli膰 V, Stein GH, Far DF, Reed SI (1998) Nuclear accumulation of p21Cip1 at the onset of mitosis: a role at the G2/M-phase transition. Mol Cell Biol 18(1):546鈥?57
66. El Golli Bennour E, Rodriguez-Enfedaque A, Bouaziz C, Ladjimi M, Renaud F, Bacha H (2009) Toxicities induced in cultured human hepatocarcinoma cells exposed to ochratoxin A: oxidative stress and apoptosis status. J Biochem Mol Toxicol 23(2):87鈥?6. doi:10.1002/jbt.20268
67. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75(4):817鈥?25
68. Farmer PB, Singh R, Kaur B, Sram RJ, Binkova B, Kalina I, Popov TA, Garte S, Taioli E, Gabelova A, Cebulska-Wasilewska A (2003) Molecular epidemiology studies of carcinogenic environmental pollutants. Effects of polycyclic aromatic hydrocarbons (PAHs) in environmental pollution on exogenous and oxidative DNA damage. Mutat Res 544(2鈥?):397鈥?02
69. Faustman EM, Ponce RA, Ou YC, Mendoza MA, Lewandowski T, Kavanagh T (2002) Investigations of methylmercury-induced alterations in neurogenesis. Environ Health Perspect 110(Suppl 5):859鈥?64
70. Flores-Rozas H, Kelman Z, Dean FB, Pan ZQ, Harper JW, Elledge SJ, O鈥橠onnell M, Hurwitz J (1994) Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme. Proc Natl Acad Sci USA 91(18):8655鈥?659
71. Fontana L, Fiori ME, Albini S, Cifaldi L, Giovinazzi S, Forloni M, Boldrini R, Donfrancesco A, Federici V, Giacomini P, Peschle C, Fruci D (2008) Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS ONE 3(5):e2236. doi:10.1371/journal.pone.0002236
72. Fotedar R, Fitzgerald P, Rousselle T, Cannella D, Dor茅e M, Messier H, Fotedar A (1996) p21 contains independent binding sites for cyclin and cdk2: both sites are required to inhibit cdk2 kinase activity. Oncogene 12(10):2155鈥?164
73. Fritah A, Saucier C, Mester J, Redeuilh G, Sabbah M (2005) p21WAF1/CIP1 selectively controls the transcriptional activity of estrogen receptor alpha. Mol Cell Biol 25(6):2419鈥?430. doi:10.1128/MCB.25.6.2419-2430.2005
74. Frouin I, Maga G, Denegri M, Riva F, Savio M, Spadari S, Prosperi E, Scovassi AI (2003) Human proliferating cell nuclear antigen, poly(ADP-ribose) polymerase-1, and p21waf1/cip1. A dynamic exchange of partners. J Biol Chem 278(41):39265鈥?9268. doi:10.1074/jbc.C300098200
75. Fujiwara K, Daido S, Yamamoto A, Kobayashi R, Yokoyama T, Aoki H, Iwado E, Shinojima N, Kondo Y, Kondo S (2008) Pivotal role of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in apoptosis and autophagy. J Biol Chem 283(1):388鈥?97
76. Gao L, Shen JB, Sun J, Shan BE (2007) Effect of the venom of the spider Macrothele raveni on the expression of p21 gene in HepG2 cells. Sheng Li Xue Bao 59(1):58鈥?2
77. Garner E, Raj K (2008) Protective mechanisms of p53鈥損21鈥損Rb proteins against DNA damage-induced cell death. Cell Cycle 7(3):277鈥?82
78. Gartel AL (2005) The conflicting roles of the cdk inhibitor p21(CIP1/WAF1) in apoptosis. Leuk Res 29(11):1237鈥?238
79. Gartel AL, Tyner AL (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1(8):639鈥?49
80. Gartel AL, Serfas MS, Gartel M, Goufman E, Wu GS, el-Deiry WS, Tyner AL (1996) p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line. Exp Cell Res 227(2):171鈥?81. doi:10.1006/excr.1996.0264
81. Gehen SC, Vitiello PF, Bambara RA, Keng PC, O鈥橰eilly MA (2007) Downregulation of PCNA potentiates p21-mediated growth inhibition in response to hyperoxia. Am J Physiol Lung Cell Mol Physiol 292(3):L716鈥揕724. doi:10.1152/ajplung.00135.2006
82. Gervais JL, Seth P, Zhang H (1998) Cleavage of CDK inhibitor p21(Cip1/Waf1) by caspases is an early event during DNA damage-induced apoptosis. J Biol Chem 273(30):19207鈥?9212
83. Giles KM, Daly JM, Beveridge DJ, Thomson AM, Voon DC, Furneaux HM, Jazayeri JA, Leedman PJ (2003) The 3鈥?untranslated region of p21WAF1 mRNA is a composite cis-acting sequence bound by RNA-binding proteins from breast cancer cells, including HuR and poly(C)-binding protein. J Biol Chem 278(5):2937鈥?946. doi:10.1074/jbc.M208439200
84. Gillis LD, Leidal AM, Hill R, Lee PW (2009) p21Cip1/WAF1 mediates cyclin B1 degradation in response to DNA damage. Cell Cycle 8(2):253鈥?56
85. Gorjala P, Gary RK (2010) Beryllium sulfate induces p21 CDKN1A expression and a senescence-like cell cycle arrest in susceptible cancer cell types. Biometals 23(6):1061鈥?073. doi:10.1007/s10534-010-9352-y
86. Gottifredi V, McKinney K, Poyurovsky MV, Prives C (2004) Decreased p21 levels are required for efficient restart of DNA synthesis after S phase block. J Biol Chem 279(7):5802鈥?810. doi:10.1074/jbc.M310373200
87. Goubin F, Ducommun B (1995) Identification of binding domains on the p21Cip1 cyclin-dependent kinase inhibitor. Oncogene 10(12):2281鈥?287
88. Gregory DJ, Garcia-Wilson E, Poole JC, Snowden AW, Roninson IB, Perkins ND (2002) Induction of transcription through the p300 CRD1 motif by p21WAF1/CIP1 is core promoter specific and cyclin dependent kinase independent. Cell Cycle 1(5):343鈥?50
89. Guindon-Kezis KA, Mulder JE, Massey TE (2014) In vivo treatment with aflatoxin B1 increases DNA oxidation, base excision repair activity and 8-oxoguanine DNA glycosylase 1 levels in mouse lung. Toxicology 321:21鈥?6. doi:10.1016/j.tox.2014.03.004
90. Gulbis JM, Kelman Z, Hurwitz J, O鈥橠onnell M, Kuriyan J (1996) Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Cell 87(2):297鈥?06
91. Gursoy-Yuzugullu O, Yuzugullu H, Yilmaz M, Ozturk M (2011) Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation. Liver Int 31(4):561鈥?71. doi:10.1111/j.1478-3231.2011.02474.x
92. Halder B, Das Gupta S, Gomes A (2012) Black tea polyphenols induce human leukemic cell cycle arrest by inhibiting Akt signaling: possible involvement of Hsp90, Wnt/尾-catenin signaling and FOXO1. FEBS J 279(16):2876鈥?891. doi:10.1111/j.1742-4658.2012.08668.x
93. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75(4):805鈥?16
94. Harvey KJ, Lukovic D, Ucker DS (2000) Caspase-dependent Cdk activity is a requisite effector of apoptotic death events. J Cell Biol 148(1):59鈥?2
95. Havens CG, Walter JC (2009) Docking of a specialized PIP Box onto chromatin-bound PCNA creates a degron for the ubiquitin ligase CRL4Cdt2. Mol Cell 35(1):93鈥?04. doi:10.1016/j.molcel.2009.05.012
96. He X, Duan C, Chen J, Ou-Yang X, Zhang Z, Li C, Peng H (2009) Let-7a elevates p21(WAF1) levels by targeting of NIRF and suppresses the growth of A549 lung cancer cells. FEBS Lett 583(21):3501鈥?507. doi:10.1016/j.febslet.2009.10.007
97. Helt CE, Staversky RJ, Lee YJ, Bambara RA, Keng PC, O鈥橰eilly MA (2004) The Cdk and PCNA domains on p21Cip1 both function to inhibit G1/S progression during hyperoxia. Am J Physiol Lung Cell Mol Physiol 286(3):L506鈥揕513
98. Heo JI, Oh SJ, Kho YJ, Kim JH, Kang HJ, Park SH, Kim HS, Shin JY, Kim MJ, Kim SC, Park JB, Kim J, Lee JY (2011) ERK mediates anti-apoptotic effect through phosphorylation and cytoplasmic localization of p21Waf1/Cip1/Sdi in response to DNA damage in normal human embryonic fibroblast (HEF) cells. Mol Biol Rep 38(4):2785鈥?791. doi:10.1007/s11033-010-0423-5
99. Herbig U, Sedivy JM (2006) Regulation of growth arrest in senescence: telomere damage is not the end of the story. Mech Ageing Dev 127(1):16鈥?4. doi:10.1016/j.mad.2005.09.002
100. Hern谩ndez-Zavala A, C贸rdova E, Del Razo LM, Cebri谩n ME, Garrido E (2005) Effects of arsenite on cell cycle progression in a human bladder cancer cell line. Toxicology 207(1):49鈥?7. doi:10.1016/j.tox.2004.08.013
101. Hill R, Leidal AM, Madureira PA, Gillis LD, Waisman DM, Chiu A, Lee PW (2008) Chromium-mediated apoptosis: involvement of DNA-dependent protein kinase (DNA-PK) and differential induction of p53 target genes. DNA Repair (Amst) 7(9):1484鈥?499. doi:10.1016/j.dnarep.2008.05.007
102. Hreljac I, Zajc I, Lah T, Filipic M (2008) Effects of model organophosphorous pesticides on DNA damage and proliferation of HepG2 cells. Environ Mol Mutagen 49(5):360鈥?67. doi:10.1002/em.20392
103. Hsu CP, Shih YT, Lin BR, Chiu CF, Lin CC (2012) Inhibitory effect and mechanisms of an anthocyanins- and anthocyanidins-rich extract from purple-shoot tea on colorectal carcinoma cell proliferation. J Agric Food Chem 60(14):3686鈥?692. doi:10.1021/jf204619n
104. Hsu YH, Chang CC, Yang NJ, Lee YH, Juan SH (2014) RhoA-mediated inhibition of vascular endothelial cell mobility: positive feedback through reduced cytosolic p21 and p27. J Cell Physiol 229(10):1455鈥?465. doi:10.1002/jcp.24583
105. Hu YC, Hsieh BS, Cheng HL, Huang LW, Huang TC, Huang IY, Chang KL (2013) Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Biochem Pharmacol 85(7):1018鈥?026. doi:10.1016/j.bcp.2013.01.008
106. Hwang CY, Kim IY, Kwon KS (2007) Cytoplasmic localization and ubiquitination of p21(Cip1) by reactive oxygen species. Biochem Biophys Res Commun 358(1):219鈥?25
107. Hwang CY, Lee C, Kwon KS (2009) Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21Cip1. Mol Cell Biol 29(12):3379鈥?389. doi:10.1128/MCB.01758-08
108. Hyun Park W, Hee Cho Y, Won Jung C, Oh Park J, Kim K, Hyuck Im Y, Lee MH, Ki Kang W, Park K (2003) Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell cycle arrest or apoptosis. Biochem Biophys Res Commun 300(1):230鈥?35
109. Iavicoli I, Cufino V, Corbi M, Goracci M, Caredda E, Cittadini A, Bergamaschi A, Sgambato A (2012) Rhodium and iridium salts inhibit proliferation and induce DNA damage in rat fibroblasts in vitro. Toxicol In Vitro 26(6):963鈥?69. doi:10.1016/j.tiv.2012.03.014
110. Ichida JK, Julia TCW, Williams LA, Carter AC, Shi Y, Moura MT, Ziller M, Singh S, Amabile G, Bock C, Umezawa A, Rubin LL, Bradner JE, Akutsu H, Meissner A, Eggan K (2014) Notch inhibition allows oncogene-independent generation of iPS cells. Nat Chem Biol 10(8):632鈥?39. doi:10.1038/nchembio.1552
111. Ip SW, Wei HC, Lin JP, Kuo HM, Liu KC, Hsu SC, Yang JS, Mei-Dueyang, Chiu TH, Han SM, Chung JG (2008) Bee venom induced cell cycle arrest and apoptosis in human cervical epidermoid carcinoma Ca Ski cells. Anticancer Res 28(2A):833鈥?42
112. Ivanovska I, Ball AS, Diaz RL, Magnus JF, Kibukawa M, Schelter JM, Kobayashi SV, Lim L, Burchard J, Jackson AL, Linsley PS, Cleary MA (2008) MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol Cell Biol 28(7):2167鈥?174. doi:10.1128/MCB.01977-07
113. Jakob B, Scholz M, Taucher-Scholz G (2002) Characterization of CDKN1A (p21) binding to sites of heavy-ion-induced damage: colocalization with proteins involved in DNA repair. Int J Radiat Biol 78(2):75鈥?8. doi:10.1080/09553000110090007
114. J盲nicke RU, Sohn D, Essmann F, Schulze-Osthoff K (2007) The multiple battles fought by anti-apoptotic p21. Cell Cycle 6(4):407鈥?13
115. Jascur T, Fotedar R, Greene S, Hotchkiss E, Boland CR (2011) N-methyl-N鈥?nitro-N-nitrosoguanidine (MNNG) triggers MSH2 and Cdt2 protein-dependent degradation of the cell cycle and mismatch repair (MMR) inhibitor protein p21Waf1/Cip1. J Biol Chem 286(34):29531鈥?9539. doi:10.1074/jbc.M111.221341
116. Jin YH, Yoo KJ, Lee YH, Lee SK (2000) Caspase 3-mediated cleavage of p21WAF1/CIP1 associated with the cyclin A-cyclin-dependent kinase 2 complex is a prerequisite for apoptosis in SK-HEP-1 cells. J Biol Chem 275(39):30256鈥?0263. doi:10.1074/jbc.M001902200
117. Jin Y, Lee H, Zeng SX, Dai MS, Lu H (2003) MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J 22(23):6365鈥?377. doi:10.1093/emboj/cdg600
118. Johnson NF, Jaramillo RJ (1997) p53, Cip1, and Gadd153 expression following treatment of A549 cells with natural and man-made vitreous fibers. Environ Health Perspect 105(Suppl 5):1143鈥?145
119. Johnson NF, Carpenter TR, Jaramillo RJ, Liberati TA (1997) DNA damage-inducible genes as biomarkers for exposures to environmental agents. Environ Health Perspect 105(Suppl 4):913鈥?18
120. Joseph B, Orlian M, Furneaux H (1998) p21(waf1) mRNA contains a conserved element in its 3鈥?untranslated region that is bound by the Elav-like mRNA-stabilizing proteins. J Biol Chem 273(32):20511鈥?0516
121. Jung YS, Qian Y, Chen X (2010) Examination of the expanding pathways for the regulation of p21 expression and activity. Cell Signal 22(7):1003鈥?012. doi:10.1016/j.cellsig.2010.01.013
122. Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, Gonos ES, Thrasivoulou C, Saffrey MJ, Cameron K, von Zglinicki T (2012) Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11(6):996鈥?004
123. Kang SJ, Kim BM, Lee YJ, Chung HW (2008) Titanium dioxide nanoparticles trigger p53-mediated damage response in peripheral blood lymphocytes. Environ Mol Mutagen 49(5):399鈥?05. doi:10.1002/em.20399 ; doi:10.1111/j.1474-9726.2012.00870.x
124. Kao PN, Chen L, Brock G, Ng J, Kenny J, Smith AJ, Corth茅sy B (1994) Cloning and expression of cyclosporin A- and FK506-sensitive nuclear factor of activated T-cells: NF45 and NF90. J Biol Chem 269(32):20691鈥?0699
125. Katsiki M, Trougakos IP, Chondrogianni N, Alexopoulos EC, Makropoulos V, Gonos ES (2004) Alterations of senescence biomarkers in human cells by exposure to CrVI in vivo and in vitro. Exp Gerontol 39(7):1079鈥?087. doi:10.1016/j.exger.2004.03.039
126. Kawanishi S, Hiraku Y, Murata M, Oikawa S (2002) The role of metals in site-specific DNA damage with reference to carcinogenesis. Free Radic Biol Med 32(9):822鈥?32
127. Kim GY, Mercer SE, Ewton DZ, Yan Z, Jin K, Friedman E (2002) The stress-activated protein kinases p38 alpha and JNK1 stabilize p21(Cip1) by phosphorylation. J Biol Chem 277(33):29792鈥?9802. doi:10.1074/jbc.M201299200
128. Kim H, Kokkotou E, Na X, Rhee SH, Moyer MP, Pothoulakis C, Lamont JT (2005) Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Gastroenterology 129(6):1875鈥?888. doi:10.1053/j.gastro.2005.09.011
129. Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, Hur K, Yoo MW, Lee HJ, Yang HK, Kim VN (2009) Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res 37(5):1672鈥?681. doi:10.1093/nar/gkp002
130. Kim HS, Heo JI, Park SH, Shin JY, Kang HJ, Kim MJ, Kim SC, Kim J, Park JB, Lee JY (2014a) Transcriptional activation of p21(WAF1/CIP1) is mediated by increased DNA binding activity and increased interaction between p53 and Sp1 via phosphorylation during replicative senescence of human embryonic fibroblasts. Mol Biol Rep 41(4):2397鈥?408. doi:10.1007/s11033-014-3094-9
131. Kim JY, Yi BR, Go RE, Hwang KA, Nam KH, Choi KC (2014b) Methoxychlor and triclosan stimulates ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an estrogen receptor-dependent pathway. Environ Toxicol Pharmacol 37(3):1264鈥?274. doi:10.1016/j.etap.2014.04.013
132. Kippin TE, Martens DJ, van der Kooy D (2005) p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev 19(6):756鈥?67. doi:10.1101/gad.1272305
133. Kitaura H, Shinshi M, Uchikoshi Y, Ono T, Iguchi-Ariga SM, Ariga H (2000) Reciprocal regulation via protein-protein interaction between c-Myc and p21(cip1/waf1/sdi1) in DNA replication and transcription. J Biol Chem 275(14):10477鈥?0483
134. Koike M, Yutoku Y, Koike A (2011) Accumulation of p21 proteins at DNA damage sites independent of p53 and core NHEJ factors following irradiation. Biochem Biophys Res Commun 412(1):39鈥?3. doi:10.1016/j.bbrc.2011.07.032
135. Komissarova EV, Rossman TG (2010) Arsenite induced poly(ADP-ribosyl)ation of tumor suppressor P53 in human skin keratinocytes as a possible mechanism for carcinogenesis associated with arsenic exposure. Toxicol Appl Pharmacol 243(3):399鈥?04. doi:10.1016/j.taap.2009.12.014
136. Kraljevic Pavelic S, Cacev T, Kralj M (2008) A dual role of p21waf1/cip1 gene in apoptosis of HEp-2 treated with cisplatin or methotrexate. Cancer Gene Ther 15(9):576鈥?90. doi:10.1038/cgt.2008.28
137. Kreis NN, Sanhaji M, Rieger MA, Louwen F, Yuan J (2013) p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells. Oncogene. doi:10.1038/onc.2013.518
138. Kreis NN, Louwen F, Yuan J (2014) Less understood issues: p21(Cip1) in mitosis and its therapeutic potential. Oncogene. doi:10.1038/onc.2014.133
139. Kriwacki RW, Hengst L, Tennant L, Reed SI, Wright PE (1996) Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Proc Natl Acad Sci USA 93(21):11504鈥?1509
140. Kumar R, Ansari KM, Chaudhari BP, Dhawan A, Dwivedi PD, Jain SK, Das M (2012) Topical application of ochratoxin A causes DNA damage and tumor initiation in mouse skin. PLoS ONE 7(10):e47280. doi:10.1371/journal.pone.0047280
141. Kumari G, Ulrich T, Gaubatz S (2013) A role for p38 in transcriptional elongation of p21 (CIP1) in response to Aurora B inhibition. Cell Cycle 12(13):2051鈥?060. doi:10.4161/cc.25100
142. LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E (1997) New functional activities for the p21 family of CDK inhibitors. Genes Dev 11(7):847鈥?62
143. Lafarga V, Cuadrado A, Lopez de Silanes I, Bengoechea R, Fernandez-Capetillo O, Nebreda AR (2009) p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21(Cip1) mRNA mediates the G(1)/S checkpoint. Mol Cell Biol 29(16):4341鈥?351. doi:10.1128/MCB.00210-09
144. Langley B, D鈥橝nnibale MA, Suh K, Ayoub I, Tolhurst A, Bastan B, Yang L, Ko B, Fisher M, Cho S, Beal MF, Ratan RR (2008) Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21(waf1/cip1) in cell cycle-independent neuroprotection. J Neurosci 28(1):163鈥?76. doi:10.1523/JNEUROSCI.3200-07.2008
145. Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, Lodish HF, Lim B (2009) MicroRNA-125b is a novel negative regulator of p53. Genes Dev 23(7):862鈥?76. doi:10.1101/gad.1767609
146. Lee S, Helfman DM (2004) Cytoplasmic p21Cip1 is involved in Ras-induced inhibition of the ROCK/LIMK/cofilin pathway. J Biol Chem 279(3):1885鈥?891. doi:10.1074/jbc.M306968200
147. Lee J, Kim JA, Barbier V, Fotedar A, Fotedar R (2009a) DNA damage triggers p21WAF1-dependent Emi1 down-regulation that maintains G2 arrest. Mol Biol Cell 20(7):1891鈥?902. doi:10.1091/mbc.E08-08-0818
148. Lee JY, Kim HS, Kim JY, Sohn J (2009b) Nuclear translocation of p21(WAF1/CIP1) protein prior to its cytosolic degradation by UV enhances DNA repair and survival. Biochem Biophys Res Commun 390(4):1361鈥?366. doi:10.1016/j.bbrc.2009.10.160
149. Lee J, Hoi CS, Lilja KC, White BS, Lee SE, Shalloway D, Tumbar T (2013) Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo. Proc Natl Acad Sci USA 110(12):4634鈥?639. doi:10.1073/pnas.1213015110
150. Lee HR, Hwang KA, Nam KH, Kim HC, Choi KC (2014a) Progression of breast cancer cells was enhanced by endocrine-disrupting chemicals, triclosan and octylphenol, via an estrogen receptor-dependent signaling pathway in cellular and mouse xenograft models. Chem Res Toxicol 27(5):834鈥?42. doi:10.1021/tx5000156
151. Lee HR, Kim TH, Choi KJ, Choi KC (2014b) Effects of octylphenol on the expression of cell cycle-related genes and the growth of mesenchymal stem cells derived from human umbilical cord blood. Int J Mol Med 33(1):221鈥?26. doi:10.3892/ijmm.2013.1556
152. Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R (1998) Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Mol Cell 1(4):553鈥?63
153. Levresse V, Renier A, Fleury-Feith J, Levy F, Moritz S, Vivo C, Pilatte Y, Jaurand MC (1997) Analysis of cell cycle disruptions in cultures of rat pleural mesothelial cells exposed to asbestos fibers. Am J Respir Cell Mol Biol 17(6):660鈥?71. doi:10.1165/ajrcmb.17.6.2854
154. Li Y, Dowbenko D, Lasky LA (2002) AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem 277(13):11352鈥?1361. doi:10.1074/jbc.M109062200
155. Li Y, Yin W, Wang X, Zhu W, Huang Y, Yan G (2007a) Cholera toxin induces malignant glioma cell differentiation via the PKA/CREB pathway. Proc Natl Acad Sci USA 104(33):13438鈥?3443. doi:10.1073/pnas.0701990104
156. Li M, Zhang Z, Hill DL, Wang H, Zhang R (2007b) Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3聽K/mTOR/ETS2 pathway. Cancer Res 67(5):1988鈥?996
157. Li Q, Lambrechts MJ, Zhang Q, Liu S, Ge D, Yin R, Xi M, You Z (2013a) Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis. Drug Des Dev Ther 7:635鈥?43. doi:10.2147/DDDT.S49197
158. Li Y, Hu J, Guan F, Song L, Fan R, Zhu H, Hu X, Shen E, Yang B (2013b) Copper induces cellular senescence in human glioblastoma multiforme cells through downregulation of Bmi-1. Oncol Rep 29(5):1805鈥?810. doi:10.3892/or.2013.2333
159. Lin J, Reichner C, Wu X, Levine AJ (1996) Analysis of wild-type and mutant p21WAF-1 gene activities. Mol Cell Biol 16(4):1786鈥?793
160. Liu ZM, Huang HS (2008) Arsenic trioxide phosphorylates c-Fos to transactivate p21(WAF1/CIP1) expression. Toxicol Appl Pharmacol 233(2):297鈥?07. doi:10.1016/j.taap.2008.08.015
161. Liu S, Bishop WR, Liu M (2003) Differential effects of cell cycle regulatory protein p21(WAF1/Cip1) on apoptosis and sensitivity to cancer chemotherapy. Drug Resist Updat 6(4):183鈥?95
162. Liu L, Lee S, Zhang J, Peters SB, Hannah J, Zhang Y, Yin Y, Koff A, Ma L, Zhou P (2009) CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis. Mol Cell 34(4):451鈥?60. doi:10.1016/j.molcel.2009.04.020
163. Liu J, Yang Y, Zhang Y, Liu W (2011) Disrupting effects of bifenthrin on ovulatory gene expression and prostaglandin synthesis in rat ovarian granulosa cells. Toxicology 282(1鈥?):47鈥?5. doi:10.1016/j.tox.2011.01.007
164. Lunghi P, Costanzo A, Levrero M, Bonati A (2004) Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73鈥損53AIP1 apoptotic pathway in leukemia cells. Blood 104(2):519鈥?25
165. Luo Y, Hurwitz J, Massagu茅 J (1995) Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature 375(6527):159鈥?61. doi:10.1038/375159a0
166. Maccario C, Savio M, Ferraro D, Bianchi L, Pizzala R, Pretali L, Forti L, Stivala LA (2012) The resveratrol analog 4,4鈥?dihydroxy-trans-stilbene suppresses transformation in normal mouse fibroblasts and inhibits proliferation and invasion of human breast cancer cells. Carcinogenesis 33(11):2172鈥?180. doi:10.1093/carcin/bgs244
167. Mally A (2012) Ochratoxin a and mitotic disruption: mode of action analysis of renal tumor formation by ochratoxin A. Toxicol Sci 127(2):315鈥?30. doi:10.1093/toxsci/kfs105
168. Mandal M, Bandyopadhyay D, Goepfert TM, Kumar R (1998) Interferon-induces expression of cyclin-dependent kinase-inhibitors p21WAF1 and p27Kip1 that prevent activation of cyclin-dependent kinase by CDK-activating kinase (CAK). Oncogene 16(2):217鈥?25. doi:10.1038/sj.onc.1201529
169. Manente L, Sellitti A, Lucariello A, Laforgia V, De Falco M, De Luca A (2011) Effects of 4-nonylphenol on proliferation of AGS gastric cells. Cell Prolif 44(5):477鈥?85. doi:10.1111/j.1365-2184.2011.00774.x
170. Mantel C, Braun SE, Reid S, Henegariu O, Liu L, Hangoc G, Broxmeyer HE (1999) p21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polyploidy, and relaxed microtubule damage checkpoints in human hematopoietic cells. Blood 93(4):1390鈥?398
171. Marqu茅s-Torrej贸n M, Porlan E, Banito A, G贸mez-Ibarlucea E, Lopez-Contreras AJ, Fern谩ndez-Capetillo O, Vidal A, Gil J, Torres J, Fari帽as I (2013) Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression. Cell Stem Cell 12(1):88鈥?00. doi:10.1016/j.stem.2012.12.001
172. Martinez LA, Yang J, Vazquez ES, Rodriguez-Vargas Mdel C, Olive M, Hsieh JT, Logothetis CJ, Navone NM (2002) p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cells. Carcinogenesis 23(8):1289鈥?296
173. Marwick JA, Kirkham P, Gilmour PS, Donaldson K, MacNEE W, Rahman I (2002) Cigarette smoke-induced oxidative stress and TGF-beta1 increase p21waf1/cip1 expression in alveolar epithelial cells. Ann N Y Acad Sci 973:278鈥?83
174. Masgras I, Carrera S, de Verdier PJ, Brennan P, Majid A, Makhtar W, Tulchinsky E, Jones GD, Roninson IB, Macip S (2012) Reactive oxygen species and mitochondrial sensitivity to oxidative stress determine induction of cancer cell death by p21. J Biol Chem 287(13):9845鈥?854. doi:10.1074/jbc.M111.250357
175. Masih PJ, Kunnev D, Melendy T (2008) Mismatch Repair proteins are recruited to replicating DNA through interaction with Proliferating Cell Nuclear Antigen (PCNA). Nucleic Acids Res 36(1):67鈥?5. doi:10.1093/nar/gkm943
176. Matos L, Gouveia A, Almeida H (2012) Copper ability to induce premature senescence in human fibroblasts. Age (Dordr) 34(4):783鈥?94. doi:10.1007/s11357-011-9276-7
177. Mauro M, Rego MA, Boisvert RA, Esashi F, Cavallo F, Jasin M, Howlett NG (2012) p21 promotes error-free replication-coupled DNA double-strand break repair. Nucleic Acids Res 40(17):8348鈥?360. doi:10.1093/nar/gks612
178. McGrath SA (1998) Induction of p21WAF/CIP1 during hyperoxia. Am J Respir Cell Mol Biol 18(2):179鈥?87. doi:10.1165/ajrcmb.18.2.2964m
179. McGrath-Morrow SA, Stahl J (2001) Growth arrest in A549 cells during hyperoxic stress is associated with decreased cyclin B1 and increased p21(Waf1/Cip1/Sdi1) levels. Biochim Biophys Acta 1538(1):90鈥?7
180. McGrath-Morrow SA, Cho C, Soutiere S, Mitzner W, Tuder R (2004) The effect of neonatal hyperoxia on the lung of p21Waf1/Cip1/Sdi1-deficient mice. Am J Respir Cell Mol Biol 30(5):635鈥?40. doi:10.1165/rcmb.2003-0049OC
181. Mendoza MA, Ponce RA, Ou YC, Faustman EM (2002) p21(WAF1/CIP1) inhibits cell cycle progression but not G2/M-phase transition following methylmercury exposure. Toxicol Appl Pharmacol 178(2):117鈥?25. doi:10.1006/taap.2001.9267
182. Mergenthaler P, Muselmann C, S眉nwoldt J, Isaev NK, Wieloch T, Dirnagl U, Meisel A, Ruscher K (2013) A functional role of the cyclin-dependent kinase inhibitor 1 (p21(WAF1/CIP1)) for neuronal preconditioning. J Cereb Blood Flow Metab 33(3):351鈥?55. doi:10.1038/jcbfm.2012.213
183. Michishita M, Morimoto A, Ishii T, Komori H, Shiomi Y, Higuchi Y, Nishitani H (2011) Positively charged residues located downstream of PIP box, together with TD amino acids within PIP box, are important for CRL4(Cdt2) -mediated proteolysis. Genes Cells 16(1):12鈥?2. doi:10.1111/j.1365-2443.2010.01464.x
184. Moldovan GL, Pfander B, Jentsch S (2007) PCNA, the maestro of the replication fork. Cell 129(4):665鈥?79. doi:10.1016/j.cell.2007.05.003
185. Mustafa Rizvi SH, Parveen A, Verma AK, Ahmad I, Arshad M, Mahdi AA (2014) Aluminium induced endoplasmic reticulum stress mediated cell death in SH-SY5Y neuroblastoma cell line is independent of p53. PLoS ONE 9(5):e98409. doi:10.1371/journal.pone.0098409
186. Nandakumar V, Vaid M, Katiyar SK (2011) (鈭?-Epigallocatechin-3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis 32(4):537鈥?44. doi:10.1093/carcin/bgq285
187. Narayanan BA (2006) Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets. Curr Cancer Drug Targets 6(8):711鈥?27
188. Nasu K, Nishida M, Ueda T, Takai N, Bing S, Narahara H, Miyakawa I (2005) Bufalin induces apoptosis and the G0/G1 cell cycle arrest of endometriotic stromal cells: a promising agent for the treatment of endometriosis. Mol Hum Reprod 11(11):817鈥?23. doi:10.1093/molehr/gah249
189. Negishi Y, Ui N, Nakajima M, Kawashima K, Maruyama K, Takizawa T, Endo H (2001) p21Cip-1/SDI-1/WAF-1 gene is involved in chondrogenic differentiation of ATDC5 cells in vitro. J Biol Chem 276(35):33249鈥?3256. doi:10.1074/jbc.M010127200
190. Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T (2008) CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation. J Biol Chem 283(43):29045鈥?9052. doi:10.1074/jbc.M806045200
191. Nyunoya T, Monick MM, Klingelhutz A, Yarovinsky TO, Cagley JR, Hunninghake GW (2006) Cigarette smoke induces cellular senescence. Am J Respir Cell Mol Biol 35(6):681鈥?88
192. Oh YT, Chun KH, Park BD, Choi JS, Lee SK (2007) Regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 by protein kinase Cdelta-mediated phosphorylation. Apoptosis 12(7):1339鈥?347. doi:10.1007/s10495-007-0066-8
193. Oku T, Ikeda S, Sasaki H, Fukuda K, Morioka H, Ohtsuka E, Yoshikawa H, Tsurimoto T (1998) Functional sites of human PCNA which interact with p21 (Cip1/Waf1), DNA polymerase delta and replication factor C. Genes Cells 3(6):357鈥?69
194. O鈥橰eilly MA (2005) Redox activation of p21Cip1/WAF1/Sdi1: a multifunctional regulator of cell survival and death. Antioxid Redox Signal 7(1鈥?):108鈥?18
195. O鈥橰eilly MA, Staversky RJ, Watkins RH, Maniscalco WM (1998) Accumulation of p21(Cip1/WAF1) during hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 19(5):777鈥?85. doi:10.1165/ajrcmb.19.5.3200
196. O鈥橰eilly MA, Staversky RJ, Watkins RH, Reed CK, de Mesy Jensen KL, Finkelstein JN, Keng PC (2001) The cyclin-dependent kinase inhibitor p21 protects the lung from oxidative stress. Am J Respir Cell Mol Biol 24(6):703鈥?10
197. Ostrakhovitch EA, Cherian MG (2005) Role of p53 and reactive oxygen species in apoptotic response to copper and zinc in epithelial breast cancer cells. Apoptosis 10(1):111鈥?21. doi:10.1007/s10495-005-6066-7
198. Ou YC, Thompson SA, Ponce RA, Schroeder J, Kavanagh TJ, Faustman EM (1999) Induction of the cell cycle regulatory gene p21 (Waf1, Cip1) following methylmercury exposure in vitro and in vivo. Toxicol Appl Pharmacol 157(3):203鈥?12. doi:10.1006/taap.1999.8685
199. Paladini F, Cocco E, Potolicchio I, Fazekasova H, Lombardi G, Fiorillo MT, Sorrentino R (2011) Divergent effect of cobalt and beryllium salts on the fate of peripheral blood monocytes and T lymphocytes. Toxicol Sci 119(2):257鈥?69. doi:10.1093/toxsci/kfq328
200. Park WH, Seol JG, Kim ES, Hyun JM, Jung CW, Lee CC, Kim BK, Lee YY (2000) Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res 60(11):3065鈥?071
201. Park SY, Lee JH, Ha M, Nam JW, Kim VN (2009) miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol 16(1):23鈥?9. doi:10.1038/nsmb.1533
202. Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347. doi:10.1038/msb.2010.5
203. Pechnick RN, Zonis S, Wawrowsky K, Pourmorady J, Chesnokova V (2008) p21Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus. Proc Natl Acad Sci USA 105(4):1358鈥?363. doi:10.1073/pnas.0711030105
204. Perkins ND (2002) Not just a CDK inhibitor: regulation of transcription by p21(WAF1/CIP1/SDI1). Cell Cycle 1(1):39鈥?1
205. Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ (1997) Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science 275(5299):523鈥?27
206. Perucca P, Cazzalini O, Mortusewicz O, Necchi D, Savio M, Nardo T, Stivala LA, Leonhardt H, Cardoso MC, Prosperi E (2006) Spatiotemporal dynamics of p21CDKN1A protein recruitment to DNA-damage sites and interaction with proliferating cell nuclear antigen. J Cell Sci 119(Pt 8):1517鈥?527. doi:10.1242/jcs.02868
207. Perucca P, Cazzalini O, Madine M, Savio M, Laskey RA, Vannini V, Prosperi E, Stivala LA (2009) Loss of p21 CDKN1A impairs entry to quiescence and activates a DNA damage response in normal fibroblasts induced to quiescence. Cell Cycle 8(1):105鈥?14. doi:10.4161/cc.8.1.7507
208. Petkovi膰 J, Zegura B, Stevanovi膰 M, Drnov拧ek N, Uskokovi膰 D, Novak S, Filipi膷 M (2011) DNA damage and alterations in expression of DNA damage responsive genes induced by TiO2 nanoparticles in human hepatoma HepG2 cells. Nanotoxicology 5(3):341鈥?53. doi:10.3109/17435390.2010.507316
209. Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13(3):272鈥?86. doi:10.1016/j.ccr.2008.02.013
210. Piao CQ, Zhao YL, Hei TK (2001) Analysis of p16 and p21(Cip1) expression in tumorigenic human bronchial epithelial cells induced by asbestos. Oncogene 20(50):7301鈥?306. doi:10.1038/sj.onc.1204908
211. Poole JC, Thain A, Perkins ND, Roninson IB (2004) Induction of transcription by p21Waf1/Cip1/Sdi1: role of NFkappaB and effect of non-steroidal anti-inflammatory drugs. Cell Cycle 3(7):931鈥?40
212. Porlan E, Morante-Redolat JM, Marqu茅s-Torrej贸n M, Andreu-Agull贸 C, Carneiro C, G贸mez-Ibarlucea E, Soto A, Vidal A, Ferr贸n SR, Fari帽as I (2013) Transcriptional repression of Bmp2 by p21(Waf1/Cip1) links quiescence to neural stem cell maintenance. Nat Neurosci 16(11):1567鈥?575. doi:10.1038/nn.3545
213. Prives C, Gottifredi V (2008) The p21 and PCNA partnership: a new twist for an old plot. Cell Cycle 7(24):3840鈥?846
214. Prosperi E (2006) The fellowship of the rings: distinct pools of proliferating cell nuclear antigen trimer at work. FASEB J 20(7):833鈥?37. doi:10.1096/fj.05-5469hyp
215. Rancourt RC, Keng PC, Helt CE, O鈥橰eilly MA (2001) The role of p21(CIP1/WAF1) in growth of epithelial cells exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol 280(4):L617鈥揕626
216. Ricordy R, Gensabella G, Cacci E, Augusti-Tocco G (2002) Impairment of cell cycle progression by aflatoxin B1 in human cell lines. Mutagenesis 17(3):241鈥?49
217. Rodr铆guez-Vilarrupla A, D铆az C, Canela N, Rahn HP, Bachs O, Agell N (2002) Identification of the nuclear localization signal of p21(cip1) and consequences of its mutation on cell proliferation. FEBS Lett 531(2):319鈥?23
218. Romanov VS, Pospelov VA, Pospelova TV (2012) Cyclin-dependent kinase inhibitor p21(Waf1): contemporary view on its role in senescence and oncogenesis. Biochemistry (Mosc) 77(6):575鈥?84. doi:10.1134/S000629791206003X
219. Rong JJ, Hu R, Qi Q, Gu HY, Zhao Q, Wang J, Mu R, You QD, Guo QL (2009) Gambogic acid down-regulates MDM2 oncogene and induces p21(Waf1/CIP1) expression independent of p53. Cancer Lett 284(1):102鈥?12. doi:10.1016/j.canlet.2009.04.011
220. Roninson IB (2002) Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. Cancer Lett 179(1):1鈥?4
221. R枚ssig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM, Dimmeler S (2001) Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol Cell Biol 21(16):5644鈥?657. doi:10.1128/MCB.21.16.5644-5657.2001
222. R枚ssig L, Badorff C, Holzmann Y, Zeiher AM, Dimmeler S (2002) Glycogen synthase kinase-3 couples AKT-dependent signaling to the regulation of p21Cip1 degradation. J Biol Chem 277(12):9684鈥?689. doi:10.1074/jbc.M106157200
223. Rossner P, Binkova B, Milcova A, Solansky I, Zidzik J, Lyubomirova KD, Farmer PB, Sram RJ (2007) Air pollution by carcinogenic PAHs and plasma levels of p53 and p21(WAF1) proteins. Mutat Res 620(1鈥?):34鈥?0. doi:10.1016/j.mrfmmm.2007.02.020
224. Roy S, Khanna S, Bickerstaff AA, Subramanian SV, Atalay M, Bierl M, Pendyala S, Levy D, Sharma N, Venojarvi M, Strauch A, Orosz CG, Sen CK (2003) Oxygen sensing by primary cardiac fibroblasts: a key role of p21(Waf1/Cip1/Sdi1). Circ Res 92(3):264鈥?71
225. Roy R, Singh SK, Chauhan LK, Das M, Tripathi A, Dwivedi PD (2014) Zinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3聽K/Akt/mTOR inhibition. Toxicol Lett 227(1):29鈥?0. doi:10.1016/j.toxlet.2014.02.024
226. Rusin M, Butkiewicz D, Malusecka E, Zborek A, Harasim J, Czyzewski K, Bennett WP, Shields PG, Weston A, Welsh JA, Krzyzowska-Gruca S, Chorazy M, Harris CC (1999) Molecular epidemiological study of non-small-cell lung cancer from an environmentally polluted region of Poland. Br J Cancer 80(9):1445鈥?452. doi:10.1038/sj.bjc.6690542
227. Russo AA, Jeffrey PD, Patten AK, Massagu茅 J, Pavletich NP (1996) Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382(6589):325鈥?31. doi:10.1038/382325a0
228. Saiz-Ladera C, Lara MF, Gar铆n M, Ruiz S, Santos M, Lorz C, Garc铆a-Escudero R, Mart铆nez-Fern谩ndez M, Bravo A, Fern谩ndez-Capetillo O, Segrelles C, Paramio JM (2014) p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia. Oncogene 33(37):4599鈥?612. doi:10.1038/onc.2013.417
229. Sakai R, Kondo C, Oka H, Miyajima H, Kubo K, Uehara T (2014) Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology 315:8鈥?6. doi:10.1016/j.tox.2013.10.009
230. Santucci MA, Mercatali L, Brusa G, Pattacini L, Barbieri E, Perocco P (2003) Cell-cycle deregulation in BALB/c 3T3 cells transformed by 1,2-dibromoethane and folpet pesticides. Environ Mol Mutagen 41(5):315鈥?21. doi:10.1002/em.10162
231. Sappino AP, Buser R, Lesne L, Gimelli S, B茅na F, Belin D, Mandriota SJ (2012) Aluminium chloride promotes anchorage-independent growth in human mammary epithelial cells. J Appl Toxicol 32(3):233鈥?43. doi:10.1002/jat.1793
232. Satapathy SR, Mohapatra P, Preet R, Das D, Sarkar B, Choudhuri T, Wyatt MD, Kundu CN (2013) Silver-based nanoparticles induce apoptosis in human colon cancer cells mediated through p53. Nanomedicine (Lond) 8(8):1307鈥?322. doi:10.2217/nnm.12.176
233. Sato T, Koseki T, Yamato K, Saiki K, Konishi K, Yoshikawa M, Ishikawa I, Nishihara T (2002) p53-independent expression of p21(CIP1/WAF1) in plasmacytic cells during G(2) cell cycle arrest induced by Actinobacillus actinomycetemcomitans cytolethal distending toxin. Infect Immun 70(2):528鈥?34
234. Satyanarayana A, Hilton MB, Kaldis P (2008) p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint. Mol Biol Cell 19(1):65鈥?7. doi:10.1091/mbc.E07-06-0525
235. Savio M, Coppa T, Cazzalini O, Perucca P, Necchi D, Nardo T, Stivala LA, Prosperi E (2009) Degradation of p21CDKN1A after DNA damage is independent of type of lesion, and is not required for DNA repair. DNA Repair (Amst) 8(7):778鈥?85. doi:10.1016/j.dnarep.2009.02.005
236. Saxena N, Ansari KM, Kumar R, Dhawan A, Dwivedi PD, Das M (2009) Patulin causes DNA damage leading to cell cycle arrest and apoptosis through modulation of Bax, p(53) and p(21/WAF1) proteins in skin of mice. Toxicol Appl Pharmacol 234(2):192鈥?01. doi:10.1016/j.taap.2008.09.033
237. Scatizzi JC, Mavers M, Hutcheson J, Young B, Shi B, Pope RM, Ruderman EM, Samways DS, Corbett JA, Egan TM, Perlman H (2009) The CDK domain of p21 is a suppressor of IL-1beta-mediated inflammation in activated macrophages. Eur J Immunol 39(3):820鈥?25. doi:10.1002/eji.200838683
238. Scott MT, Morrice N, Ball KL (2000) Reversible phosphorylation at the C-terminal regulatory domain of p21(Waf1/Cip1) modulates proliferating cell nuclear antigen binding. J Biol Chem 275(15):11529鈥?1537
239. Seol JG, Park WH, Kim ES, Jung CW, Hyun JM, Kim BK, Lee YY (1999) Effect of arsenic trioxide on cell cycle arrest in head and neck cancer cell line PCI-1. Biochem Biophys Res Commun 265(2):400鈥?04. doi:10.1006/bbrc.1999.1697
240. Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM, Clurman BE (2000) Proteasomal turnover of p21Cip1 does not require p21Cip1 ubiquitination. Mol Cell 5(2):403鈥?10
241. Shim J, Lee H, Park J, Kim H, Choi EJ (1996) A non-enzymatic p21 protein inhibitor of stress-activated protein kinases. Nature 381(6585):804鈥?06. doi:10.1038/381804a0
242. Shin SY, Kim CG, Lim Y, Lee YH (2011) The ETS family transcription factor ELK-1 regulates induction of the cell cycle-regulatory gene p21(Waf1/Cip1) and the BAX gene in sodium arsenite-exposed human keratinocyte HaCaT cells. J Biol Chem 286(30):26860鈥?6872. doi:10.1074/jbc.M110.216721
243. Shiyanov P, Bagchi S, Adami G, Kokontis J, Hay N, Arroyo M, Morozov A, Raychaudhuri P (1996) p21 Disrupts the interaction between cdk2 and the E2F-p130 complex. Mol Cell Biol 16(3):737鈥?44
244. Shu L, Yan W, Chen X (2006) RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript. Genes Dev 20(21):2961鈥?972. doi:10.1101/gad.1463306
245. Smits VA, Klompmaker R, Vallenius T, Rijksen G, M盲kela TP, Medema RH (2000) p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. J Biol Chem 275(39):30638鈥?0643. doi:10.1074/jbc.M005437200
246. Sohn D, Essmann F, Schulze-Osthoff K, J盲nicke RU (2006) p21 blocks irradiation-induced apoptosis downstream of mitochondria by inhibition of cyclin-dependent kinase-mediated caspase-9 activation. Cancer Res 66(23):11254鈥?1262. doi:10.1158/0008-5472.CAN-06-1569
247. Sohn YD, Cho KS, Sun SA, Sung HJ, Kwak KW, Hong SY, Kim DS, Chung KH (2008) Suppressive effect and mechanism of saxatilin, a disintegrin from Korean snake (Gloydius saxatilis), in vascular smooth muscle cells. Toxicon 52(3):474鈥?80. doi:10.1016/j.toxicon.2008.06.020
248. Sohn D, Budach W, J盲nicke RU (2011) Caspase-2 is required for DNA damage-induced expression of the CDK inhibitor p21(WAF1/CIP1). Cell Death Differ 18(10):1664鈥?674. doi:10.1038/cdd.2011.34
249. Solhaug A, Vines LL, Ivanova L, Spilsberg B, Holme JA, Pestka J, Collins A, Eriksen GS (2012) Mechanisms involved in alternariol-induced cell cycle arrest. Mutat Res 738鈥?39:1鈥?1. doi:10.1016/j.mrfmmm.2012.09.001
250. Soria G, Gottifredi V (2010) PCNA-coupled p21 degradation after DNA damage: the exception that confirms the rule? DNA Repair (Amst) 9(4):358鈥?64. doi:10.1016/j.dnarep.2009.12.003
251. Soria G, Speroni J, Podhajcer OL, Prives C, Gottifredi V (2008) p21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation. J Cell Sci 121(Pt 19):3271鈥?282. doi:10.1242/jcs.027730
252. Spencer SL, Cappell SD, Tsai FC, Overton KW, Wang CL, Meyer T (2013) The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 155(2):369鈥?83. doi:10.1016/j.cell.2013.08.062
253. Srivastava RK, Rahman Q, Kashyap MP, Singh AK, Jain G, Jahan S, Lohani M, Lantow M, Pant AB (2013) Nano-titanium dioxide induces genotoxicity and apoptosis in human lung cancer cell line, A549. Hum Exp Toxicol 32(2):153鈥?66. doi:10.1177/0960327112462725
254. Starostina NG, Simpliciano JM, McGuirk MA, Kipreos ET (2010) CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells. Dev Cell 19(5):753鈥?64. doi:10.1016/j.devcel.2010.10.013
255. Staversky RJ, Vitiello PF, Gehen SC, Helt CE, Rahman A, Keng PC, O鈥橰eilly MA (2006) p21(Cip1/Waf1/Sdi1) protects against hyperoxia by maintaining expression of Bcl-X(L). Free Radic Biol Med 41(4):601鈥?09. doi:10.1016/j.freeradbiomed.2006.04.029
256. Stivala LA, Savio M, Quarta S, Scotti C, Cazzalini O, Rossi L, Scovassi IA, Pizzala R, Melli R, Bianchi L, Vannini V, Prosperi E (2000) The antiproliferative effect of beta-carotene requires p21waf1/cip1 in normal human fibroblasts. Eur J Biochem 267(8):2290鈥?296
257. Stivala LA, Riva F, Cazzalini O, Savio M, Prosperi E (2001a) p21(waf1/cip1)-null human fibroblasts are deficient in nucleotide excision repair downstream the recruitment of PCNA to DNA repair sites. Oncogene 20(5):563鈥?70. doi:10.1038/sj.onc.1204132
258. Stivala LA, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi E, Vannini V (2001b) Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J Biol Chem 276(25):22586鈥?2594. doi:10.1074/jbc.M101846200
259. Stivala LA, Cazzalini O, Prosperi E (2012) The cyclin-dependent kinase inhibitor p21CDKN1A as a target of anti-cancer drugs. Curr Cancer Drug Targets 12(2):85鈥?6
260. Straser A, Filipi膷 M, Zegura B (2011) Genotoxic effects of the cyanobacterial hepatotoxin cylindrospermopsin in the HepG2 cell line. Arch Toxicol 85(12):1617鈥?626. doi:10.1007/s00204-011-0716-z
261. Sunkaria A, Wani WY, Sharma DR, Gill KD (2013) Dichlorvos-induced cell cycle arrest and DNA damage repair activation in primary rat microglial cells. J Neurosci Res 91(3):444鈥?52. doi:10.1002/jnr.23173
262. Suzuki T, Tsukamoto I (2005) Manganese-induced apoptosis in hepatocytes after partial hepatectomy. Eur J Pharmacol 525(1鈥?):48鈥?3. doi:10.1016/j.ejphar.2005.09.061
263. Suzuki A, Tsutomi Y, Akahane K, Araki T, Miura M (1998) Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. Oncogene 17(8):931鈥?39. doi:10.1038/sj.onc.1202021
264. Suzuki A, Tsutomi Y, Miura M, Akahane K (1999) Caspase 3 inactivation to suppress Fas-mediated apoptosis: identification of binding domain with p21 and ILP and inactivation machinery by p21. Oncogene 18(5):1239鈥?244. doi:10.1038/sj.onc.1202409
265. Tan HH, Porter AG (2009) p21(WAF1) negatively regulates DNMT1 expression in mammalian cells. Biochem Biophys Res Commun 382(1):171鈥?76. doi:10.1016/j.bbrc.2009.03.001
266. Taylor BF, McNeely SC, Miller HL, Lehmann GM, McCabe MJ, States JC (2006) p53 suppression of arsenite-induced mitotic catastrophe is mediated by p21CIP1/WAF1. J Pharmacol Exp Ther 318(1):142鈥?51. doi:10.1124/jpet.106.103077
267. Terrand J, Xu B, Morrissy S, Dinh TN, Williams S, Chen QM (2011) p21(WAF1/Cip1/Sdi1) knockout mice respond to doxorubicin with reduced cardiotoxicity. Toxicol Appl Pharmacol 257(1):102鈥?10. doi:10.1016/j.taap.2011.08.024
268. Thakur VS, Gupta K, Gupta S (2012) Green tea polyphenols causes cell cycle arrest and apoptosis in prostate cancer cells by suppressing class I histone deacetylases. Carcinogenesis 33(2):377鈥?84. doi:10.1093/carcin/bgr277
269. Thang ND, Yajima I, Kumasaka MY, Kato M (2014) Bidirectional functions of arsenic as a carcinogen and an anti-cancer agent in human squamous cell carcinoma. PLoS ONE 9(5):e96945. doi:10.1371/journal.pone.0096945
270. Tillhon M, Cazzalini O, Nardo T, Necchi D, Sommatis S, Stivala LA, Scovassi AI, Prosperi E (2012) p300/CBP acetyl transferases interact with and acetylate the nucleotide excision repair factor XPG. DNA Repair (Amst) 11(10):844鈥?52. doi:10.1016/j.dnarep.2012.08.001
271. Tillhon M, Cazzalini O, Dutto I, Stivala LA, Prosperi E (2013) p21CDKN1A and DNA repair systems: recent findings and future perspectives. In: Chen C (ed) DNA repair鈥攏ew research directions. InTech,聽Rijeka, pp 249鈥?79
272. Tom S, Ranalli TA, Podust VN, Bambara RA (2001) Regulatory roles of p21 and apurinic/apyrimidinic endonuclease 1 in base excision repair. J Biol Chem 276(52):48781鈥?8789. doi:10.1074/jbc.M109626200
273. Tomita K, Caramori G, Lim S, Ito K, Hanazawa T, Oates T, Chiselita I, Jazrawi E, Chung KF, Barnes PJ, Adcock IM (2002) Increased p21(CIP1/WAF1) and B cell lymphoma leukemia-x(L) expression and reduced apoptosis in alveolar macrophages from smokers. Am J Respir Crit Care Med 166(5):724鈥?31
274. Topley GI, Okuyama R, Gonzales JG, Conti C, Dotto GP (1999) p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Proc Natl Acad Sci USA 96(16):9089鈥?094
275. Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ (2001) A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome. EMBO J 20(10):2367鈥?375. doi:10.1093/emboj/20.10.2367
276. Traka MH, Chambers KF, Lund EK, Goodlad RA, Johnson IT, Mithen RF (2009) Involvement of KLF4 in sulforaphane- and iberin-mediated induction of p21(waf1/cip1). Nutr Cancer 61(1):137鈥?45. doi:10.1080/01635580802348641
277. Trakala M, Arias CF, Garc铆a MI, Moreno-Ortiz MC, Tsilingiri K, Fern谩ndez PJ, Mellado M, D铆az-Meco MT, Moscat J, Serrano M, Mart铆nez-A C, Balomenos D (2009) Regulation of macrophage activation and septic shock susceptibility via p21(WAF1/CIP1). Eur J Immunol 39(3):810鈥?19. doi:10.1002/eji.200838676
278. Trakala M, Fern谩ndez-Miranda G, P茅rez de Castro I, Heeschen C, Malumbres M (2013) Aurora B prevents delayed DNA replication and premature mitotic exit by repressing p21(Cip1). Cell Cycle 12(7):1030鈥?041. doi:10.4161/cc.24004
279. Tsuji T, Aoshiba K, Nagai A (2004) Cigarette smoke induces senescence in alveolar epithelial cells. Am J Respir Cell Mol Biol 31(6):643鈥?49. doi:10.1165/rcmb.2003-0290OC
280. Umar A, Buermeyer AB, Simon JA, Thomas DC, Clark AB, Liskay RM, Kunkel TA (1996) Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87(1):65鈥?3
281. Urani C, Melchioretto P, Fabbri M, Bowe G, Maserati E, Gribaldo L (2014) Cadmium Impairs p53 Activity in HepG2 Cells. ISRN Toxicol 2014:976428. doi:10.1155/2014/976428
282. Viale A, De Franco F, Orleth A, Cambiaghi V, Giuliani V, Bossi D, Ronchini C, Ronzoni S, Muradore I, Monestiroli S, Gobbi A, Alcalay M, Minucci S, Pelicci PG (2009) Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457(7225):51鈥?6. doi:10.1038/nature07618
283. Visanji JM, Duthie SJ, Pirie L, Thompson DG, Padfield PJ (2004) Dietary isothiocyanates inhibit Caco-2 cell proliferation and induce G2/M phase cell cycle arrest, DNA damage, and G2/M checkpoint activation. J Nutr 134(11):3121鈥?126
284. Vitiello PF, Staversky RJ, Gehen SC, Johnston CJ, Finkelstein JN, Wright TW, O鈥橰eilly MA (2006) p21Cip1 protection against hyperoxia requires Bcl-XL and is uncoupled from its ability to suppress growth. Am J Pathol 168(6):1838鈥?847. doi:10.2353/ajpath.2006.051162
285. Vitiello PF, Wu YC, Staversky RJ, O鈥橰eilly MA (2009) p21(Cip1) protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways. Free Radic Biol Med 46(1):33鈥?1. doi:10.1016/j.freeradbiomed.2008.09.022
286. Vogt BL, Rossman TG (2001) Effects of arsenite on p53, p21 and cyclin D expression in normal human fibroblasts - a possible mechanism for arsenite鈥檚 comutagenicity. Mutat Res 478(1鈥?):159鈥?68
287. Waga S, Hannon GJ, Beach D, Stillman B (1994) The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 369(6481):574鈥?78. doi:10.1038/369574a0
288. Waldman T, Lengauer C, Kinzler KW, Vogelstein B (1996) Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381(6584):713鈥?16. doi:10.1038/381713a0
289. Wang G, Hazra TK, Mitra S, Lee HM, Englander EW (2000a) Mitochondrial DNA damage and a hypoxic response are induced by CoCl(2) in rat neuronal PC12 cells. Nucleic Acids Res 28(10):2135鈥?140
290. Wang W, Furneaux H, Cheng H, Caldwell MC, Hutter D, Liu Y, Holbrook N, Gorospe M (2000b) HuR regulates p21 mRNA stabilization by UV light. Mol Cell Biol 20(3):760鈥?69
291. Wang W, Nacusi L, Sheaff RJ, Liu X (2005) Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection. Biochemistry 44(44):14553鈥?4564. doi:10.1021/bi051071j
292. Warbrick E (1998) PCNA binding through a conserved motif. BioEssays 20(3):195鈥?99. doi:10.1002/(SICI)1521-1878(199803)20:3<195:AID-BIES2>3.0.CO;2-R
293. Warbrick E, Lane DP, Glover DM, Cox LS (1995) A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen. Curr Biol 5(3):275鈥?82
294. Warfel NA, El-Deiry WS (2013) p21WAF1 and tumourigenesis: 20聽years after. Curr Opin Oncol 25(1):52鈥?8. doi:10.1097/CCO.0b013e32835b639e
295. Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q, Wu Y, Jiang H, Sun X (2013) STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal 25(4):931鈥?38. doi:10.1016/j.cellsig.2013.01.011
296. Welcker M, Lukas J, Strauss M, Bartek J (1998) p21WAF1/CIP1 mutants deficient in inhibiting cyclin-dependent kinases (CDKs) can promote assembly of active cyclin D/CDK4(6) complexes in human tumor cells. Cancer Res 58(22):5053鈥?056
297. Wiese C, Rudolph JH, Jakob B, Fink D, Tobias F, Blattner C, Taucher-Scholz G (2012) PCNA-dependent accumulation of CDKN1A into nuclear foci after ionizing irradiation. DNA Repair (Amst) 11(5):511鈥?21. doi:10.1016/j.dnarep.2012.02.006
298. Wohlschlegel JA, Dwyer BT, Takeda DY, Dutta A (2001) Mutational analysis of the Cy motif from p21 reveals sequence degeneracy and specificity for different cyclin-dependent kinases. Mol Cell Biol 21(15):4868鈥?874. doi:10.1128/MCB.21.15.4868-4874.2001
299. Wong VC, Morse JL, Zhitkovich A (2013) p53 activation by Ni(II) is a HIF-1伪 independent response causing caspases 9/3-mediated apoptosis in human lung cells. Toxicol Appl Pharmacol 269(3):233鈥?39. doi:10.1016/j.taap.2013.03.023
300. Wu YC, O鈥橰eilly MA (2011) Bcl-X(L) is the primary mediator of p21 protection against hyperoxia-induced cell death. Exp Lung Res 37(2):82鈥?1. doi:10.3109/01902148.2010.521617
301. Wu J, Sun J (2011) Investigation on mechanism of growth arrest induced by iron oxide nanoparticles in PC12 cells. J Nanosci Nanotechnol 11(12):11079鈥?1083
302. Wu CC, Lin JP, Yang JS, Chou ST, Chen SC, Lin YT, Lin HL, Chung JG (2006) Capsaicin induced cell cycle arrest and apoptosis in human esophagus epidermoid carcinoma CE 81T/VGH cells through the elevation of intracellular reactive oxygen species and Ca2聽+聽productions and caspase-3 activation. Mutat Res 601(1鈥?):71鈥?2. doi:10.1016/j.mrfmmm.2006.06.015
303. Wu QK, Koponen JM, Mykk盲nen HM, T枚rr枚nen AR (2007) Berry phenolic extracts modulate the expression of p21(WAF1) and Bax but not Bcl-2 in HT-29 colon cancer cells. J Agric Food Chem 55(4):1156鈥?163. doi:10.1021/jf062320t
304. Xia M, Knezevic D, Vassilev LT (2011) p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation. Oncogene 30(3):346鈥?55. doi:10.1038/onc.2010.413
305. Yang X, Wang W, Fan J, Lal A, Yang D, Cheng H, Gorospe M (2004) Prostaglandin A2-mediated stabilization of p21 mRNA through an ERK-dependent pathway requiring the RNA-binding protein HuR. J Biol Chem 279(47):49298鈥?9306. doi:10.1074/jbc.M407535200
306. Yang H, Chung DH, Kim YB, Choi YH, Moon Y (2008) Ribotoxic mycotoxin deoxynivalenol induces G2/M cell cycle arrest via p21Cip/WAF1 mRNA stabilization in human epithelial cells. Toxicology 243(1鈥?):145鈥?54. doi:10.1016/j.tox.2007.10.002
307. Yano M, Okano HJ, Okano H (2005) Involvement of Hu and heterogeneous nuclear ribonucleoprotein K in neuronal differentiation through p21 mRNA post-transcriptional regulation. J Biol Chem 280(13):12690鈥?2699. doi:10.1074/jbc.M411119200
308. Yao H, Yang SR, Edirisinghe I, Rajendrasozhan S, Caito S, Adenuga D, O鈥橰eilly MA, Rahman I (2008) Disruption of p21 attenuates lung inflammation induced by cigarette smoke, LPS, and fMLP in mice. Am J Respir Cell Mol Biol 39(1):7鈥?8. doi:10.1165/rcmb.2007-0342OC
309. Yao H, Sundar IK, Gorbunova V, Rahman I (2013) P21-PARP-1 pathway is involved in cigarette smoke-induced lung DNA damage and cellular senescence. PLoS ONE 8(11):e80007. doi:10.1371/journal.pone.0080007
310. Ye Y, Liu J, Chen M, Sun L, Lan M (2010) In vitro toxicity of silica nanoparticles in myocardial cells. Environ Toxicol Pharmacol 29(2):131鈥?37. doi:10.1016/j.etap.2009.12.002
311. Yih LH, Lee TC (2000) Arsenite induces p53 accumulation through an ATM-dependent pathway in human fibroblasts. Cancer Res 60(22):6346鈥?352
312. Yu SY, Liao CH, Chien MH, Tsai TY, Lin JK, Weng MS (2014) Induction of p21(Waf1/Cip1) by garcinol via downregulation of p38-MAPK signaling in p53-independent H1299 lung cancer. J Agric Food Chem 62(9):2085鈥?095. doi:10.1021/jf4037722
313. Zezula J, Casaccia-Bonnefil P, Ezhevsky SA, Osterhout DJ, Levine JM, Dowdy SF, Chao MV, Koff A (2001) p21cip1 is required for the differentiation of oligodendrocytes independently of cell cycle withdrawal. EMBO Rep 2(1):27鈥?4. doi:10.1093/embo-reports/kve008
314. Zhan J, Easton JB, Huang S, Mishra A, Xiao L, Lacy ER, Kriwacki RW, Houghton PJ (2007) Negative regulation of ASK1 by p21Cip1 involves a small domain that includes Serine 98 that is phosphorylated by ASK1 in vivo. Mol Cell Biol 27(9):3530鈥?541. doi:10.1128/MCB.00086-06
315. Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ (1999) p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. Genes Dev 13(2):213鈥?24
316. Zhang Z, Wang H, Li M, Agrawal S, Chen X, Zhang R (2004) MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem 279(16):16000鈥?6006. doi:10.1074/jbc.M312264200
317. Zhang J, Ghio AJ, Gao M, Wei K, Rosen GD, Upadhyay D (2007) Ambient particulate matter induces alveolar epithelial cell cycle arrest: role of G1 cyclins. FEBS Lett 581(27):5315鈥?320. doi:10.1016/j.febslet.2007.10.020
318. Zhang Y, Gao JS, Tang X, Tucker LD, Quesenberry P, Rigoutsos I, Ramratnam B (2009) MicroRNA 125a and its regulation of the p53 tumor suppressor gene. FEBS Lett 583(22):3725鈥?730. doi:10.1016/j.febslet.2009.10.002
319. Zhang D, Cui Y, Shen H, Xing L, Cui J, Wang J, Zhang X (2013a) Sterigmatocystin-induced DNA damage triggers G2 arrest via an ATM/p53-related pathway in human gastric epithelium GES-1 cells in vitro. PLoS ONE 8(5):e65044. doi:10.1371/journal.pone.0065044
320. Zhang L, Sang H, Liu Y, Li J (2013b) Manganese activates caspase-9-dependent apoptosis in human bronchial epithelial cells. Hum Exp Toxicol 32(11):1155鈥?163. doi:10.1177/0960327112470272
321. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3(3):245鈥?52. doi:10.1038/35060032
322. Zhu W, Abbas T, Dutta A (2005) DNA replication and genomic instability. Adv Exp Med Biol 570:249鈥?79. doi:10.1007/1-4020-3764-3_9
323. Zurlo D, Assante G, Moricca S, Colantuoni V, Lupo A (2014) Cladosporol A, a new peroxisome proliferator-activated receptor 纬 (PPAR纬) ligand, inhibits colorectal cancer cells proliferation through 尾-catenin/TCF pathway inactivation. Biochim Biophys Acta 1840(7):2361鈥?372. doi:10.1016/j.bbagen.2014.04.007 - 刊物主题：Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine general;
- 出版者：Springer Berlin Heidelberg
- ISSN：1432-0738
文摘
The cell cycle inhibitor p21CDKN1A is a protein playing multiple roles not only in the DNA damage response, but also in many cellular processes during unperturbed cell growth. The main, well-known function of p21 is to arrest cell cycle progression by inhibiting the activity of cyclin-dependent kinases. In addition, p21 is involved in the regulation of transcription, apoptosis, DNA repair, as well as cell motility. However, p21 appears to a have a dual-face behavior because, in addition to its tumor suppressor functions, it may act as an oncogene, depending on the cell type and on the cellular localization. As a biomarker of the cell response to different toxic stimuli, p21 expression and functions have been analyzed in an impressive number of studies investigating the activity of several types of chemicals, in order to determine their possible harmful effects on human cells. Here, we review these studies in order to highlight the different roles p21 may play in the cell response to chemical exposure and to better evaluate the information provided by this biomarker.