p300通过组蛋白乙酰化修饰激活RASSF2基因表达并诱导胃癌细胞晚期凋亡
摘要
RASSF2是一个新发现的肿瘤抑制因子,是Ras相关信号通路中的负调控因子。很多证据表明,RASSF2与肿瘤的发生存在着密切的关联,在结肠癌、胃癌和鼻咽癌等癌变组织或肿瘤细胞中RASSF2是低表达的,但是在正常组织或细胞中RASSF2的表达却很高。有研究发现,RASSF2的低表达与DNA高甲基化相关。但是目前,有关RASSF2的抑癌分子机制仍所知甚少,而对于RASSF2基因表达调控的机制也了解不多。在本文中,我们发现组蛋白乙酰转移酶p300通过上调RASSF2的表达,抑制了胃癌细胞SGC-7901的增殖并对其可能的机制进行了深入的研究。我们的工作证实,过量表达p300能抑制胃癌细胞的增殖,并诱导细胞发生晚期凋亡;而这一过程可通过利用small interfering RNA (siRNA)降低RASSF2蛋白的表达水平而被逆转。染色质免疫沉淀(ChIP)实验证实,p300固有的乙酰转移酶活性在p300参与RASSF2的表达调控中是必需的;p300通过增强RASSF2启动子区域的组蛋白H3和H4的乙酰化水平促进RASSF2基因的启动子活性。而且p300和转录因子Sp1对RASSF2基因在启动子水平,mRNA水平及蛋白水平的表达具有协同激活的效果。针对Sp1和p300设计的siRNA能够通过部分地抑制Sp1和p300的表达而抑制RASSF2启动子的活性,并使RASSF2的mRNA和蛋白表达水平下降。ChIP的实验结果表明,转录因子Sp1能够促进p300被招募到RASSF2的启动子上,而过表达p300能够导致更多的转录因子Sp1与RASSF2启动子结合。我们推测,这可能与p300通过提高启动子处组蛋白H3和H4的乙酰化水平,使染色质结构变得更为松散有关。我们的研究工作将有助于更好的阐述RASSF2基因转录调控及其抑癌的分子机制,并为基于RASSF2的基因治疗提供一定的理论基础。
RASSF2, a novel tumor-suppressor gene, is a member of Ras-associated protein family that negatively regulates Ras signaling. There has been increasing evidence that RASSF2 gene is related to tumorgenesis. In colorectal cancer (CRC) cells, gastric cancer cells, and nasopharyngeal cancer cells, the level of RASSF2 expression is lower, compared to normal tissues or cells. But little is known of the mechanism of RASSF2 gene regulation and its effect on inhibiting cell proliferation. In this study, we demonstrated that p300 was able to arrest cell proliferation and induce late apoptosis in gastric cancer cells SGC-7901; and this process was reversed by RASSF2 silencing through small interference RNA (siRNA). We showed that p300 participated in activation of RASSF2 expression in 293T and SGC-7901 cells. The chromatin immunoprecipitation (ChIP) assays verified that the intrinsic histone acetyltransferase (HAT) activity of p300 was essential for RASSF2 promoter activation through inducing the hyperacetylation of histone H3 and H4 at the RASSF2 promoter. Moreover, p300 cooperated with Sp1 to stimulate RASSF2 promoter activity, and increase its mRNA and protein expression. The siRNA-induced partial silencing of Sp1 and p300 resulted in a significant inhibition of RASSF2 promoter activity. The ChIP assays revealed that the ectopic expression of p300 promoted Sp1 binding to P2 and P3 and P4 regions of RASSF2A promoter. Meanwhile, the recruitment of p300 on the P2 and P3 regions was also enhanced significantly after Sp1 overexpression. These data will contribute to elucidating the mechanisms of RASSF2 transcriptional control and its ability of suppressing cancer cells proliferation, which is crucial to the development of new therapeutic strategies for RASSF2-related gene therapy.
RASSF2, a novel tumor-suppressor gene, is a member of Ras-associated protein family that negatively regulates Ras signaling. There has been increasing evidence that RASSF2 gene is related to tumorgenesis. In colorectal cancer (CRC) cells, gastric cancer cells, and nasopharyngeal cancer cells, the level of RASSF2 expression is lower, compared to normal tissues or cells. But little is known of the mechanism of RASSF2 gene regulation and its effect on inhibiting cell proliferation. In this study, we demonstrated that p300 was able to arrest cell proliferation and induce late apoptosis in gastric cancer cells SGC-7901; and this process was reversed by RASSF2 silencing through small interference RNA (siRNA). We showed that p300 participated in activation of RASSF2 expression in 293T and SGC-7901 cells. The chromatin immunoprecipitation (ChIP) assays verified that the intrinsic histone acetyltransferase (HAT) activity of p300 was essential for RASSF2 promoter activation through inducing the hyperacetylation of histone H3 and H4 at the RASSF2 promoter. Moreover, p300 cooperated with Sp1 to stimulate RASSF2 promoter activity, and increase its mRNA and protein expression. The siRNA-induced partial silencing of Sp1 and p300 resulted in a significant inhibition of RASSF2 promoter activity. The ChIP assays revealed that the ectopic expression of p300 promoted Sp1 binding to P2 and P3 and P4 regions of RASSF2A promoter. Meanwhile, the recruitment of p300 on the P2 and P3 regions was also enhanced significantly after Sp1 overexpression. These data will contribute to elucidating the mechanisms of RASSF2 transcriptional control and its ability of suppressing cancer cells proliferation, which is crucial to the development of new therapeutic strategies for RASSF2-related gene therapy.
引文
[1]王秀莉.组蛋白乙酰转移酶p300对人p16~(INK4a)基因表达调控的影响及其分子机制研究。东北师范大学博士学位论文,2007.
[2]冯云鹏.因子ZBP-89、YY1通过抑制p16~( INK4a)基因表达影响细胞的衰老。东北师范大学硕士学位论文,2008.
[3] Lo K, Cheung ST, Leung SF, et al. Hypermethylation of the p16 gene in nasopharyngeal carcinoma [J]. Cancer Res, 1996, 56: 2721.
[4] Martinez D B, Fernandez P J , Garcia M J , et al. Hypermeth lation of 5’-CpG island of p 16 is a frequent event in non-Hodgkin’s lymphoma [J]. Leukemia, 1997, 11: 425.
[5] Du J, Wang QS , et al. MTS1/ p16 gene deleton and 5’CpG island methylation in Renal cell carcinoma [J]. Cancer prevention res, 2002, 29: 306- 307.
[6] Quesnel B, Preudhomme C, Lepelley P, et al. Transfer of p16ink4a/CDKN2 gene in leukaemic cell lines inhibits cell proliferation [J]. British J H Aematology, 1996, 95: 291- 298.
[7] Allfrey VG, Faulkner RM, Misky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis [J]. Proc Natl Acad Sci USA, 1964, 51:786-793.
[8] Ohtani N, Yamakoshi K, Takahashi A, et al. The p16INK4a/RB pathway: molecular link between cellular senescence and tumor suppression [J]. J Med Invest, 2004, 51: 146-153.
[9] Xue LX, Li J, Zhang ZY, et al. Cell senescence and transcriptional regulation of p16ink4a [J]. J Med Mol Biol, 2006, 3: 29-31.
[10] Benanti JA, Galloway DA. The normal response to RAS: senescence or transformation [J]? Cell Cycle, 2004, 3: 715-717.
[11] Berger SL. Gene activation by histone and factor acetyltransferases [J]. Curr Opin Cell Biol, 1999, 11:336-341.
[12] Cress WD, Seto E. Histone Deacetylases, transcriptional control and cancer [J]. J Cell Physiol, 2000, 184:1-16.
[13] Wu C. Chromatin remodeling and the control of gene expression [J]. J Biol Chem, 1997, 272:28171-4.
[14] Peterson CL. HDAC's at work: everyone doing their part [J]. Mol Cell, 2002, 9:921-2.
[15] Turner BM. Histone acetylation and an epigenetic code [J]. Bioessays, 2000, 22:836-45.
[16] Peterson CL, Logie C. Recruitment of chromatin remodeling machines [J]. J Cell Biochem, 2000, 78:179-85.
[17] Allis CD, Chicoine LG, Richman R, et al. Deposition-related histone acetylation in micromuclei of conjugating Tetrahymena [J]. Proc Natl Acad Sci USA, 1985, 82: 8048-8052.
[18] Grunstein M. Histone acetylation in chromatin structure and transcription [J]. Nature, 1997, 389:349-352.
[19] Fletcher TM, Hansen JC. The nucleosomal array: structure /function relationships [J]. Crit Rev Eukaryote Gene Expr, 1996, 6:149-188.
[20] Brownell JE, Zhou J, Ranalli T, et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation [J]. Cell, 1996, 84: 843-851.
[21] Smith ER, Allis CD, Lucchesi JC. Linking global histone acetylation to the transcription enhancement of X-chromosomal genes in Drosophila males [J]. J Biol Chem, 2001, 276: 31483- 31466.
[22] Lusser A, Kolle D, Loidl P. Histone acetylation: lessons from the plant kingdom [J]. Trends Plant Sci,2001, 6:59-65.
[23] Chen X, Korenberg JR. Localisation of human CREBBP to 16p13.3 by fluorescence in situ hybridization [J]. Cytogenet Cell Genet, 1995, 71:56-57.
[24] Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP [J]. Nature, 1995, 376:348-351.
[25] Eckner R, Ewen ME, Newsome D, et al. Molecular cloning and functional analysis of the adenovirus E1A-associated 300-KD protein (p300) reveals a protein with properties of a transcriptional adaptor [J]. Genes Dev, 1994, 8:869-884.
[26] Chrivia JC, Kwok RP, Lamb N,et al. Phosphorylated CREB binds specifically to the nuclear protein CBP [J]. Nature, 1993, 365:855-859.
[27] Arany Z, Sellers W R, Livingston D M, et al. E1A associated p300 and CREB-associated CBP belong to a conserved family of co-activators [J]. Cell, 1994, 77:799-800.
[28] Livengood JA, Scoggin KE, Van OK, et al. P53 trancscriptional activity is mediated through the SRC-1 interacting Domain of CBP/p300[J]. J Biol Chem, 2002,277: 9054-9061.
[29] Giles R H, Dauwerse H G, Van Ommen GB, et al. Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins [J]? Am J Hum Genet, 1997, 63:1240-1242.
[30] Enwang WANG, Xiaolong YANG. p300/CBP and Lung Cancer [J]. Chin J Lung Canc e r, 2009, 12:926-930.
[31] Zeng L, Zhang Q, Gerona-Navarro G, et al. Structural basis of site-specific histone recognition by the bromodomains of human coactivators PCAF and CBP/p300[J]. Structure, 2008,16:643-652.
[32] Chan HM, La Thangue NB. p300/CBP proteins: HATs for transcriptional bridges and scaffolds[J]. J Cell Sci,2001,114:2363-2373.
[33] Giles R H, Dauwerse H G, Van Ommen GB, et al. Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins [J]? Am J Hum Genet, 1997, 63:1240-1242.
[34] Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP [J]. Nature, 1995, 376:348-351.
[35] Muraoka M, Konishi M, Kikuchi R, et al. p300 gene alterations in colorectal and gastric carcinomas [J]. Oncogene, 1996, 12:1565-1569.
[36] Gayther SA, Batley SJ, Linger L, et al. Mutations truncating the EP300 acetylase in human cancers [J]. Nat Genet, 2000, 24:300-303.
[37] Liu HY, Wang XM, Shan J, et al. Expression of HER2 and p300/CBP in lung cancer and their clinic significances[J]. Shandong Medical Journal, 2007,47: 27-29.
[38] Ke Z, Zhang X, Ma L, et al. Expression of DPC4/Smad4 in non-small-cell lung carcinoma and its relationship with angiogenesis[J].Neoplasma,2008,55: 323-329.
[39] Lee HJ, Lee JK, Miyake S, et al. A novel E1A-like inhibitor of differentiation (EID) family member, EID-2, suppresses transforming growth factor(TGF)-beta signaling by blocking TGF-beta-induced formation of Smad3-Smad4 complexes[J]. J Biol Chem, 2004, 279: 2666-2672.
[40] Hamamori Y, Sartorelli V, Ogryzko V. Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A [J]. Cell, 1999, 96:405-413.
[41] Chakravarti D, Ogryzko V, Kao HY, et al. A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity [J]. Cell, 1999, 96:393-403.
[42] Wang HG, Rikitake Y, Carter MC, et al. Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth [J]. J Virol, 1993, 67:476-488.
[43] Cho S, Tian Y, Benjamin TL. Binding of p300/CBP co-activators by polyoma large T antigen [J]. J Biol Chem, 2001, 276:33533-33539.
[44] Georges SA, Giebler HA, Cole PA, et al. Tax recruitment of CBP/p300, via the KIX domain, reveals a potent requirement for acetyltransferase activity that is chromatin dependent and histone tailindependent [J]. Mol Cell Biol, 2003, 23:3392-3404.
[45] Wang XC, Li XX, Sun RQ, et al. The expression of cyclinD1 and P21WAF1/CIP1 protein in lung carcinoma[J]. J Xi'an Jiaotong Univ (Med Sciences),2002, 23: 220-222.
[46] Banerjee AC, Recupero AJ, Mal A, et al. The adenovirus E1A 289R and 243R proteins inhibit the phosphorylation of p300 [J]. Oncogene, 1994, 9:1733-1737.
[47] Perkins ND, Felzien LK, Betts JC, et al. Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator [J]. Science, 1997, 275:523-527.
[48] Dyson N. The regulation of E2F by pRB-family proteins [J]. Genes Dev, 1998, 12: 2245-2262.
[49] Giles R H, Dauwerse H G, Van Ommen GB, et al. Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins [J]? Am J Hum Genet, 1997, 63:1240-1242.
[50] Yang XJ, Ogryzko VV, Nishikawa J, et al. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A [J]. Nature, 1996, 382:319-324.
[51] Rihard H, Goodma N, Sarah S, et al. CBP/p300 in cell growth, transformation, and development. Genes Dev, 2000, 14: 1553-1577.
[52] Missero C, Calautti E, Eckner R, et al. Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation [J]. Proc Natl Acad Sci USA, 1995, 92:5451-5455.
[53] Avantaggiati ML, Ogrykko V, Garner K, et al. Recruitment of p300/CBP in p53-dependent signal pathways [J]. Cell, 1997, 89:1175-1184.
[54] Kawasaki H, Eckner R, Yao TP, et al. Distinct role of the co-activators p300 and CBP in retinoic-acid-induced F9-cell differentiation [J]. Nature, 1998, 393:284- 289.
[55] Lill NL, Grossman SR, Ginsberg D, et al. Binding and modulation of p53 by p300/CBP co-activators [J]. Nature, 1997, 387:823-827.
[56] Lee CW, S?rensen TS, Shikama N, et al. Functional interplay between p53 and E2F through co-activator p300 [J]. Oncogene, 1998, 16:2695-2710.
[57] Yuan W, Condorelli G, Caruso M, et al. Human p300 protein is a co-activator for the transcription factor MyoD [J]. J Biol Chem, 1996, 271:9009-9013.
[58] Grossman SR, Perez M, Kung AL, et al. p300/MDM2 complexes participate in MDM2-mediated p53 degradation [J]. Mol Cell, 1998, 2:405-415.
[59] Wang X, Taplick J, Geva N, et al. Inhibition of p53 degradation by Mdm2 acetylatio. FEBS Lett, 2004, 561(1-3): 195-201.
[60] Livengood JA, Scoggin KE, Van OK, et al. P53 trancscriptional activity is mediated through the SRC-1 interacting Domain of CBP/p300. J Biol Chem, 2002, 277(11): 9054-9061.
[61] Shikama N, Lyon J, La Thangue NB. The p300/CBP family: integrating signals with transcription factors and chromatin [J]. Trends Cell Biol, 1997, 7:230-236.
[62] Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development [J]. Genes Dev, 2000, 14:1553-1577.
[63] Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs) [J]. Oncogene, 1995, 11:211-219.
[64] Vo N, Goodman RH. CREB-binding protein and p300 in transcriptional regulation [J]. J Biol Chem,2001, 276:13505-13508.
[65] Westin S, Kurokowa R, Nolte RT, et al. Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators [J]. Nature, 1998, 305:199-202.
[66] Xu L, Glass CK, Rosenfeld MG. Co-activator and corepressor complexes in nuclear receptor function [J]. Curr Opin Genet Dev, 1999, 9:140-147.
[67] Carey M. The enhanceosome and transcriptional synergy [J]. Cell, 1998, 92:5-8.
[68] Kim TK, Kim TH, Maniatis T. Efficient recruitment of TFIIB and CBP-RNA polymerase IIholoenzyme by an interferon-beta enhanceosome in vitro [J]. Proc Natl Acad Sci USA, 1998, 95:12191-12196.
[69] Brownell JE, Allis CD. Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation [J]. Curr Opin Genet Dev, 1996, 6:176-184.
[70] Wade PA, Pruss D, Wolffe AP. Histone acetylation: chromatin in action [J]. Trends Biochem Sci, 1997, 22:128-32.
[71] Armstrong JA, Emerson BM. Transcription of chromatin: these are complex times [J]. Curr Opin Genet Dev, 1998, 8:165-172.
[72] Edmondson DG, Zhang W, Watson A, et al. In vivo functions of histone acetylation/deacetylation in Tup1p repression and Gcn5p activation [J]. Cold Spring Harbor Symp Quant Biol, 1998, 63:459-468.
[73] Schwarz PM, Felthauser A, Fletcher TM, et al. Reversible oligonucleotide self-association: dependence on divalent cations and core histone tail domains [J]. Biochemistry, 1996, 35:4009-4015.
[74] Durrin LK, Mann RK, Kayne PS, et al. Yeast histone H4 N-terminal sequence is required for promoter activation in vivo [J]. Cell, 1991, 65:1023-1031.
[75] Mizzen C, Kuo MH, Smith E, et al. Signaling to chromatin through histone modifications: how clear is the signal [J]. Cold Spring Harbor Symp Quant Biol, 1998, 63:469-481.
[76] Turner BM. Histone acetylation and control of gene expression [J]. J Cell Sci, 1991, 99:13-20.
[77] Wolffe AP, Pruss D. Targeting chromatin disruption: transcription regulators that acetylate histones [J]. Cell, 1996, 84:817-819.
[78] Lee DY, Hayes JJ, Pruss D, et al. A positive role for histone acetylation in transcription factor access to nucleosomal DNA [J]. Cell, 1993, 72:73-84.
[79] Vettese-Dadey M, Grant PA, Hebbes TR, et al. Acetylation of histone H4 plays a primary role in enhancing transcription factor binding to nucleosomal DNA in vitro [J]. EMBO J, 1996, 15:2508-2518.
[80] Luger K, Mader AW, Richmond RK, et al. Crystal structure of the nucleosome core particle at 2.8A resolution [J]. Nature, 1997, 389:251-260.
[81] Garcia-Rameriez M, Rocchini C, Ausio J. Modulation of chromatin folding by histone acetylation [J]. J Biol Chem, 1995, 270:17923-17928.
[82] Tse C, Fletcher TM, Hansen JC. Enhanced transcription factor access to arrays of histone H3/H4 tetramer. DNA complexes in vitro: implications for replication and transcription [J]. Proc Natl Acad Sci USA, 1998, 21:12169-121673.
[83] Tse C, Sera T, Wolffe AP, et al. Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III [J]. Mol Cell Biol, 1998, 18:4629-4638.
[84] Ura K, Kurumizaka H, Dimitrov S, et al. Histone acetylation: influence on transcription, nucleosome mobility and positioning, and linker histone-dependent transcriptional repression [J]. EMBO J, 1997, 16:2096-2107.
[85] Nightingale KP, Wellinger RE, Sogo JM, et al. Histone acetylation facilitates RNA polymerase II transcription of the Drosophila hsp26 gene in chromatin [J]. EMBO J, 1998, 17:2865-2875.
[86] Bevilacqua MA, Faniello MC, Russo T, et al. P/CAF/p300 complex binds the promoter for the heavy subunit of ferritin and contributes to its tissue-specific expression [J]. Biochem J, 1998, 335:521-525.
[87] Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase [J]. Nature, 1996, 384:641-643.
[88] Li Q, Herrler M, Landsberger N, et al. Xenopus NF-Y pre-sets chromatin to potentiate p300 and acetylation-responsive transcription from the Xenopus hsp70 promoter in vivo [J]. EMBO J, 1998,17:6300-6315.
[89] Li Q, Imhof A, Collingwood TN, et al. p300 stimulates transcription instigated by ligand-bound thyroid hormone receptor at a step subsequent to chromatin disruption [J]. EMBO J, 1999, 18:5634-5652.
[90] Hansen JC, Wolffe AP. A role for histones H2A/H2B in chromatin folding and transcriptional repression [J]. Proc Natl Acad Sci USA, 1994, 91:2339-2343.
[91] Nakajima T, Fukamizu A, Takahashi J, et al. The signal-dependent co-activator CBP is a nuclear target for pp90RSK [J]. Cell, 1996, 86:465-474.
[92] W. Kolch, Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions[J]. Biochem. J. 2000,351:289–305.
[93] C.P. Ponting, D.R. Benjamin, A novel family of Ras-binding domains,Trends Biochem[J]. Sci. 1996,21:422–425.
[94] T. Yamamoto, S. Taya, K. Kaibuchi, Ras-induced transformation and signaling pathway[J]. J. Biochem. 1999,126:799–803.
[95] R. Dammann, C. Li, J.H. Yoon, P.L. Chin, S. Bates, G.P. Pfeifer, Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3[J].Nat. Genet. 2000 ,25 :315–319.
[96] Louise van der Weyden , David J. Adams. The Ras-association domain family (RASSF) members and their role in human tumourigenesis[J].BBA.2007,1776,58-85.
[97] S. Comincini, B.M. Castiglioni, G.M. Foti, I. Del Vecchio, L. Ferretti, Isolation and molecular characterization of rasfadin, a novel gene in the vicinity of the bovine prion gene[J], Mamm. Genome.2001),12 :50–156.
[98] J. Loveland.VEGA, the genome browser with a difference[J]. Brief Bioinfom. 2005,6 :189–193.
[99] M.D. Vos, C.A. Ellis, C. Elam, A.S. Ulku, B.J. Taylor, G.J. Clark. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor[J]. J. Biol. Chem. 2003,278 : 28045–28051.
[100] M. Praskova, A. Khoklatchev, S. Ortiz-Vega, J. Avruch, Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins. RASSF1 and NORE1, and by Ras[J]. Biochem. J. 2004,381:453–462.
[101] L.B. Hesson, R. Wilson, D. Morton, C. Adams, M. Walker, E.R. Maher,F. Latif. CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations[J]. Oncogene 2005,24 : 3987–3994.
[102] K. Akino, M. Toyota, H. Suzuki, H. Mita, Y. Sasaki, M. Ohe-Toyota, J.P.Issa, Y. Hinoda, K. Imai, T. Tokino, The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer[J]. Gastroenterology.2005, 29:156–169.
[103] L.B. Eckert, G.A. Repasky, A.S. Ulku, A. McFall, H. Zhou, C.I. Sartor, C.J. Der. Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis[J]. Cancer Res. 2004,64 :4585–4592.
[104] K. Nosho, H. Yamamoto, T. Takahashi, M. Mikami, H. Taniguchi, N.Miyamoto, Y. Adachi, Y. Arimura, F. Itoh, K. Imai, Y. Shinomura. Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers[J].Carcinogenesis .2007,28:1364–1370.
[105] H.W. Park, H.C. Kang, I.J. Kim, S.G. Jang, K. Kim, H.J. Yoon, S.Y.Jeong, J.G. Park, Correlation between hypermethylation of the RASSF2A promoter and K-ras/BRAF mutations in microsatellite-stable colorectal cancers[J].Int. J. Cancer. 2007,120 :7–12.
[106] K. Kaira, N. Sunaga, Y. Tomizawa, N. Yanagitani, T. Ishizuka, R. Saito, T. Nakajima, M. Mori, Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers[J]. Int. J. Oncol. 2007,31:169–173.
[107] M. Endoh, G. Tamura, T. Honda, N. Homma, M. Terashima, S. Nishizuka, T. Motoyama, RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cance[J]r. Br. J. Cancer. 2005,93:1395–1399.
[108] Z. Zhang, D. Sun, N. Van do, A. Tang, L. Hu, G. Huang. Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma[J]. Int. J. Cancer. 2007,120:32–38.
[109] E.T. Sakamoto-Hojo, S.S. Mello, E. Pereira, A.L. Fachin, R.S. Cardoso, C.M. Junta, P. Sandrin-Garcia, E.A. Donadi, G.A. Passos, Gene expression profiles in human cells submitted to genotoxic stress[J]. Mutat. Res. 2003,544:403–413.
[110] Glantschnig H, Rodan GA, Reszka AA. Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. J Biol Chem 2002;277:42987–42996.
[111] K. Akino, M. Toyota, H. Suzuki, H. Mita, Y. Sasaki, M. Ohe-Toyota, J.P.Issa, Y. Hinoda, K. Imai, T. Tokino. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer[ J ]. Gastroenterology 129(2005) 156–169.
[112] Ait-Si-Ali S. Carlisi D, Ramirez S, Upegui-Gonzalez LC, Duquet A, Robin P, Rudkin B, Harel-Bellan A,Trouche D. Phosphorylation by p44 MAP kinase/ERK1 stimulates CBP histone acetyl transferase activity in vitro[ J ]. Biochem. Biophys. Res. Commun. 1999, 262: 157–162.
[113] Huang W C, Chen C C. Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity[ J ]. Mol Cell Biol. 2005 ,25:6592-602.
[114] Yuan, LW, and Gambee JE. Phosphorylation of p300 at serine 89 by protein kinase C[ J ]. J. Biol. Chem.2000, 275: 40946–40951.
[115] Missero C, Calautti E, Eckner R, Chin J, Tsai LH, Livingston DM, Dotto GP. Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation[ J ]. Proc Natl Acad Sci USA. 1995, 92: 5451-5455.
[116] Wang X, Pan L, Feng Y, Wang Y, Han Q, Han S, Guo J, Huang B, Lu J. p300 plays a role in p16(INK4a) expression and cell cycle arrest[ J ]. Oncogene. 2007, Oct 1: 1–11.
[117] Akina K, Toyota M, Suzuki H, Mita H, Sasaki Y, Ohe-Toyota M, Issa JP, Hinoda Y, Imai K, Tokino T. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer[ J ]. Gastroenterology. 2005, 129: 156-169.
[2]冯云鹏.因子ZBP-89、YY1通过抑制p16~( INK4a)基因表达影响细胞的衰老。东北师范大学硕士学位论文,2008.
[3] Lo K, Cheung ST, Leung SF, et al. Hypermethylation of the p16 gene in nasopharyngeal carcinoma [J]. Cancer Res, 1996, 56: 2721.
[4] Martinez D B, Fernandez P J , Garcia M J , et al. Hypermeth lation of 5’-CpG island of p 16 is a frequent event in non-Hodgkin’s lymphoma [J]. Leukemia, 1997, 11: 425.
[5] Du J, Wang QS , et al. MTS1/ p16 gene deleton and 5’CpG island methylation in Renal cell carcinoma [J]. Cancer prevention res, 2002, 29: 306- 307.
[6] Quesnel B, Preudhomme C, Lepelley P, et al. Transfer of p16ink4a/CDKN2 gene in leukaemic cell lines inhibits cell proliferation [J]. British J H Aematology, 1996, 95: 291- 298.
[7] Allfrey VG, Faulkner RM, Misky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis [J]. Proc Natl Acad Sci USA, 1964, 51:786-793.
[8] Ohtani N, Yamakoshi K, Takahashi A, et al. The p16INK4a/RB pathway: molecular link between cellular senescence and tumor suppression [J]. J Med Invest, 2004, 51: 146-153.
[9] Xue LX, Li J, Zhang ZY, et al. Cell senescence and transcriptional regulation of p16ink4a [J]. J Med Mol Biol, 2006, 3: 29-31.
[10] Benanti JA, Galloway DA. The normal response to RAS: senescence or transformation [J]? Cell Cycle, 2004, 3: 715-717.
[11] Berger SL. Gene activation by histone and factor acetyltransferases [J]. Curr Opin Cell Biol, 1999, 11:336-341.
[12] Cress WD, Seto E. Histone Deacetylases, transcriptional control and cancer [J]. J Cell Physiol, 2000, 184:1-16.
[13] Wu C. Chromatin remodeling and the control of gene expression [J]. J Biol Chem, 1997, 272:28171-4.
[14] Peterson CL. HDAC's at work: everyone doing their part [J]. Mol Cell, 2002, 9:921-2.
[15] Turner BM. Histone acetylation and an epigenetic code [J]. Bioessays, 2000, 22:836-45.
[16] Peterson CL, Logie C. Recruitment of chromatin remodeling machines [J]. J Cell Biochem, 2000, 78:179-85.
[17] Allis CD, Chicoine LG, Richman R, et al. Deposition-related histone acetylation in micromuclei of conjugating Tetrahymena [J]. Proc Natl Acad Sci USA, 1985, 82: 8048-8052.
[18] Grunstein M. Histone acetylation in chromatin structure and transcription [J]. Nature, 1997, 389:349-352.
[19] Fletcher TM, Hansen JC. The nucleosomal array: structure /function relationships [J]. Crit Rev Eukaryote Gene Expr, 1996, 6:149-188.
[20] Brownell JE, Zhou J, Ranalli T, et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation [J]. Cell, 1996, 84: 843-851.
[21] Smith ER, Allis CD, Lucchesi JC. Linking global histone acetylation to the transcription enhancement of X-chromosomal genes in Drosophila males [J]. J Biol Chem, 2001, 276: 31483- 31466.
[22] Lusser A, Kolle D, Loidl P. Histone acetylation: lessons from the plant kingdom [J]. Trends Plant Sci,2001, 6:59-65.
[23] Chen X, Korenberg JR. Localisation of human CREBBP to 16p13.3 by fluorescence in situ hybridization [J]. Cytogenet Cell Genet, 1995, 71:56-57.
[24] Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP [J]. Nature, 1995, 376:348-351.
[25] Eckner R, Ewen ME, Newsome D, et al. Molecular cloning and functional analysis of the adenovirus E1A-associated 300-KD protein (p300) reveals a protein with properties of a transcriptional adaptor [J]. Genes Dev, 1994, 8:869-884.
[26] Chrivia JC, Kwok RP, Lamb N,et al. Phosphorylated CREB binds specifically to the nuclear protein CBP [J]. Nature, 1993, 365:855-859.
[27] Arany Z, Sellers W R, Livingston D M, et al. E1A associated p300 and CREB-associated CBP belong to a conserved family of co-activators [J]. Cell, 1994, 77:799-800.
[28] Livengood JA, Scoggin KE, Van OK, et al. P53 trancscriptional activity is mediated through the SRC-1 interacting Domain of CBP/p300[J]. J Biol Chem, 2002,277: 9054-9061.
[29] Giles R H, Dauwerse H G, Van Ommen GB, et al. Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins [J]? Am J Hum Genet, 1997, 63:1240-1242.
[30] Enwang WANG, Xiaolong YANG. p300/CBP and Lung Cancer [J]. Chin J Lung Canc e r, 2009, 12:926-930.
[31] Zeng L, Zhang Q, Gerona-Navarro G, et al. Structural basis of site-specific histone recognition by the bromodomains of human coactivators PCAF and CBP/p300[J]. Structure, 2008,16:643-652.
[32] Chan HM, La Thangue NB. p300/CBP proteins: HATs for transcriptional bridges and scaffolds[J]. J Cell Sci,2001,114:2363-2373.
[33] Giles R H, Dauwerse H G, Van Ommen GB, et al. Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins [J]? Am J Hum Genet, 1997, 63:1240-1242.
[34] Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP [J]. Nature, 1995, 376:348-351.
[35] Muraoka M, Konishi M, Kikuchi R, et al. p300 gene alterations in colorectal and gastric carcinomas [J]. Oncogene, 1996, 12:1565-1569.
[36] Gayther SA, Batley SJ, Linger L, et al. Mutations truncating the EP300 acetylase in human cancers [J]. Nat Genet, 2000, 24:300-303.
[37] Liu HY, Wang XM, Shan J, et al. Expression of HER2 and p300/CBP in lung cancer and their clinic significances[J]. Shandong Medical Journal, 2007,47: 27-29.
[38] Ke Z, Zhang X, Ma L, et al. Expression of DPC4/Smad4 in non-small-cell lung carcinoma and its relationship with angiogenesis[J].Neoplasma,2008,55: 323-329.
[39] Lee HJ, Lee JK, Miyake S, et al. A novel E1A-like inhibitor of differentiation (EID) family member, EID-2, suppresses transforming growth factor(TGF)-beta signaling by blocking TGF-beta-induced formation of Smad3-Smad4 complexes[J]. J Biol Chem, 2004, 279: 2666-2672.
[40] Hamamori Y, Sartorelli V, Ogryzko V. Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A [J]. Cell, 1999, 96:405-413.
[41] Chakravarti D, Ogryzko V, Kao HY, et al. A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity [J]. Cell, 1999, 96:393-403.
[42] Wang HG, Rikitake Y, Carter MC, et al. Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth [J]. J Virol, 1993, 67:476-488.
[43] Cho S, Tian Y, Benjamin TL. Binding of p300/CBP co-activators by polyoma large T antigen [J]. J Biol Chem, 2001, 276:33533-33539.
[44] Georges SA, Giebler HA, Cole PA, et al. Tax recruitment of CBP/p300, via the KIX domain, reveals a potent requirement for acetyltransferase activity that is chromatin dependent and histone tailindependent [J]. Mol Cell Biol, 2003, 23:3392-3404.
[45] Wang XC, Li XX, Sun RQ, et al. The expression of cyclinD1 and P21WAF1/CIP1 protein in lung carcinoma[J]. J Xi'an Jiaotong Univ (Med Sciences),2002, 23: 220-222.
[46] Banerjee AC, Recupero AJ, Mal A, et al. The adenovirus E1A 289R and 243R proteins inhibit the phosphorylation of p300 [J]. Oncogene, 1994, 9:1733-1737.
[47] Perkins ND, Felzien LK, Betts JC, et al. Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator [J]. Science, 1997, 275:523-527.
[48] Dyson N. The regulation of E2F by pRB-family proteins [J]. Genes Dev, 1998, 12: 2245-2262.
[49] Giles R H, Dauwerse H G, Van Ommen GB, et al. Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins [J]? Am J Hum Genet, 1997, 63:1240-1242.
[50] Yang XJ, Ogryzko VV, Nishikawa J, et al. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A [J]. Nature, 1996, 382:319-324.
[51] Rihard H, Goodma N, Sarah S, et al. CBP/p300 in cell growth, transformation, and development. Genes Dev, 2000, 14: 1553-1577.
[52] Missero C, Calautti E, Eckner R, et al. Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation [J]. Proc Natl Acad Sci USA, 1995, 92:5451-5455.
[53] Avantaggiati ML, Ogrykko V, Garner K, et al. Recruitment of p300/CBP in p53-dependent signal pathways [J]. Cell, 1997, 89:1175-1184.
[54] Kawasaki H, Eckner R, Yao TP, et al. Distinct role of the co-activators p300 and CBP in retinoic-acid-induced F9-cell differentiation [J]. Nature, 1998, 393:284- 289.
[55] Lill NL, Grossman SR, Ginsberg D, et al. Binding and modulation of p53 by p300/CBP co-activators [J]. Nature, 1997, 387:823-827.
[56] Lee CW, S?rensen TS, Shikama N, et al. Functional interplay between p53 and E2F through co-activator p300 [J]. Oncogene, 1998, 16:2695-2710.
[57] Yuan W, Condorelli G, Caruso M, et al. Human p300 protein is a co-activator for the transcription factor MyoD [J]. J Biol Chem, 1996, 271:9009-9013.
[58] Grossman SR, Perez M, Kung AL, et al. p300/MDM2 complexes participate in MDM2-mediated p53 degradation [J]. Mol Cell, 1998, 2:405-415.
[59] Wang X, Taplick J, Geva N, et al. Inhibition of p53 degradation by Mdm2 acetylatio. FEBS Lett, 2004, 561(1-3): 195-201.
[60] Livengood JA, Scoggin KE, Van OK, et al. P53 trancscriptional activity is mediated through the SRC-1 interacting Domain of CBP/p300. J Biol Chem, 2002, 277(11): 9054-9061.
[61] Shikama N, Lyon J, La Thangue NB. The p300/CBP family: integrating signals with transcription factors and chromatin [J]. Trends Cell Biol, 1997, 7:230-236.
[62] Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development [J]. Genes Dev, 2000, 14:1553-1577.
[63] Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs) [J]. Oncogene, 1995, 11:211-219.
[64] Vo N, Goodman RH. CREB-binding protein and p300 in transcriptional regulation [J]. J Biol Chem,2001, 276:13505-13508.
[65] Westin S, Kurokowa R, Nolte RT, et al. Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators [J]. Nature, 1998, 305:199-202.
[66] Xu L, Glass CK, Rosenfeld MG. Co-activator and corepressor complexes in nuclear receptor function [J]. Curr Opin Genet Dev, 1999, 9:140-147.
[67] Carey M. The enhanceosome and transcriptional synergy [J]. Cell, 1998, 92:5-8.
[68] Kim TK, Kim TH, Maniatis T. Efficient recruitment of TFIIB and CBP-RNA polymerase IIholoenzyme by an interferon-beta enhanceosome in vitro [J]. Proc Natl Acad Sci USA, 1998, 95:12191-12196.
[69] Brownell JE, Allis CD. Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation [J]. Curr Opin Genet Dev, 1996, 6:176-184.
[70] Wade PA, Pruss D, Wolffe AP. Histone acetylation: chromatin in action [J]. Trends Biochem Sci, 1997, 22:128-32.
[71] Armstrong JA, Emerson BM. Transcription of chromatin: these are complex times [J]. Curr Opin Genet Dev, 1998, 8:165-172.
[72] Edmondson DG, Zhang W, Watson A, et al. In vivo functions of histone acetylation/deacetylation in Tup1p repression and Gcn5p activation [J]. Cold Spring Harbor Symp Quant Biol, 1998, 63:459-468.
[73] Schwarz PM, Felthauser A, Fletcher TM, et al. Reversible oligonucleotide self-association: dependence on divalent cations and core histone tail domains [J]. Biochemistry, 1996, 35:4009-4015.
[74] Durrin LK, Mann RK, Kayne PS, et al. Yeast histone H4 N-terminal sequence is required for promoter activation in vivo [J]. Cell, 1991, 65:1023-1031.
[75] Mizzen C, Kuo MH, Smith E, et al. Signaling to chromatin through histone modifications: how clear is the signal [J]. Cold Spring Harbor Symp Quant Biol, 1998, 63:469-481.
[76] Turner BM. Histone acetylation and control of gene expression [J]. J Cell Sci, 1991, 99:13-20.
[77] Wolffe AP, Pruss D. Targeting chromatin disruption: transcription regulators that acetylate histones [J]. Cell, 1996, 84:817-819.
[78] Lee DY, Hayes JJ, Pruss D, et al. A positive role for histone acetylation in transcription factor access to nucleosomal DNA [J]. Cell, 1993, 72:73-84.
[79] Vettese-Dadey M, Grant PA, Hebbes TR, et al. Acetylation of histone H4 plays a primary role in enhancing transcription factor binding to nucleosomal DNA in vitro [J]. EMBO J, 1996, 15:2508-2518.
[80] Luger K, Mader AW, Richmond RK, et al. Crystal structure of the nucleosome core particle at 2.8A resolution [J]. Nature, 1997, 389:251-260.
[81] Garcia-Rameriez M, Rocchini C, Ausio J. Modulation of chromatin folding by histone acetylation [J]. J Biol Chem, 1995, 270:17923-17928.
[82] Tse C, Fletcher TM, Hansen JC. Enhanced transcription factor access to arrays of histone H3/H4 tetramer. DNA complexes in vitro: implications for replication and transcription [J]. Proc Natl Acad Sci USA, 1998, 21:12169-121673.
[83] Tse C, Sera T, Wolffe AP, et al. Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III [J]. Mol Cell Biol, 1998, 18:4629-4638.
[84] Ura K, Kurumizaka H, Dimitrov S, et al. Histone acetylation: influence on transcription, nucleosome mobility and positioning, and linker histone-dependent transcriptional repression [J]. EMBO J, 1997, 16:2096-2107.
[85] Nightingale KP, Wellinger RE, Sogo JM, et al. Histone acetylation facilitates RNA polymerase II transcription of the Drosophila hsp26 gene in chromatin [J]. EMBO J, 1998, 17:2865-2875.
[86] Bevilacqua MA, Faniello MC, Russo T, et al. P/CAF/p300 complex binds the promoter for the heavy subunit of ferritin and contributes to its tissue-specific expression [J]. Biochem J, 1998, 335:521-525.
[87] Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase [J]. Nature, 1996, 384:641-643.
[88] Li Q, Herrler M, Landsberger N, et al. Xenopus NF-Y pre-sets chromatin to potentiate p300 and acetylation-responsive transcription from the Xenopus hsp70 promoter in vivo [J]. EMBO J, 1998,17:6300-6315.
[89] Li Q, Imhof A, Collingwood TN, et al. p300 stimulates transcription instigated by ligand-bound thyroid hormone receptor at a step subsequent to chromatin disruption [J]. EMBO J, 1999, 18:5634-5652.
[90] Hansen JC, Wolffe AP. A role for histones H2A/H2B in chromatin folding and transcriptional repression [J]. Proc Natl Acad Sci USA, 1994, 91:2339-2343.
[91] Nakajima T, Fukamizu A, Takahashi J, et al. The signal-dependent co-activator CBP is a nuclear target for pp90RSK [J]. Cell, 1996, 86:465-474.
[92] W. Kolch, Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions[J]. Biochem. J. 2000,351:289–305.
[93] C.P. Ponting, D.R. Benjamin, A novel family of Ras-binding domains,Trends Biochem[J]. Sci. 1996,21:422–425.
[94] T. Yamamoto, S. Taya, K. Kaibuchi, Ras-induced transformation and signaling pathway[J]. J. Biochem. 1999,126:799–803.
[95] R. Dammann, C. Li, J.H. Yoon, P.L. Chin, S. Bates, G.P. Pfeifer, Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3[J].Nat. Genet. 2000 ,25 :315–319.
[96] Louise van der Weyden , David J. Adams. The Ras-association domain family (RASSF) members and their role in human tumourigenesis[J].BBA.2007,1776,58-85.
[97] S. Comincini, B.M. Castiglioni, G.M. Foti, I. Del Vecchio, L. Ferretti, Isolation and molecular characterization of rasfadin, a novel gene in the vicinity of the bovine prion gene[J], Mamm. Genome.2001),12 :50–156.
[98] J. Loveland.VEGA, the genome browser with a difference[J]. Brief Bioinfom. 2005,6 :189–193.
[99] M.D. Vos, C.A. Ellis, C. Elam, A.S. Ulku, B.J. Taylor, G.J. Clark. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor[J]. J. Biol. Chem. 2003,278 : 28045–28051.
[100] M. Praskova, A. Khoklatchev, S. Ortiz-Vega, J. Avruch, Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins. RASSF1 and NORE1, and by Ras[J]. Biochem. J. 2004,381:453–462.
[101] L.B. Hesson, R. Wilson, D. Morton, C. Adams, M. Walker, E.R. Maher,F. Latif. CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations[J]. Oncogene 2005,24 : 3987–3994.
[102] K. Akino, M. Toyota, H. Suzuki, H. Mita, Y. Sasaki, M. Ohe-Toyota, J.P.Issa, Y. Hinoda, K. Imai, T. Tokino, The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer[J]. Gastroenterology.2005, 29:156–169.
[103] L.B. Eckert, G.A. Repasky, A.S. Ulku, A. McFall, H. Zhou, C.I. Sartor, C.J. Der. Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis[J]. Cancer Res. 2004,64 :4585–4592.
[104] K. Nosho, H. Yamamoto, T. Takahashi, M. Mikami, H. Taniguchi, N.Miyamoto, Y. Adachi, Y. Arimura, F. Itoh, K. Imai, Y. Shinomura. Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers[J].Carcinogenesis .2007,28:1364–1370.
[105] H.W. Park, H.C. Kang, I.J. Kim, S.G. Jang, K. Kim, H.J. Yoon, S.Y.Jeong, J.G. Park, Correlation between hypermethylation of the RASSF2A promoter and K-ras/BRAF mutations in microsatellite-stable colorectal cancers[J].Int. J. Cancer. 2007,120 :7–12.
[106] K. Kaira, N. Sunaga, Y. Tomizawa, N. Yanagitani, T. Ishizuka, R. Saito, T. Nakajima, M. Mori, Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers[J]. Int. J. Oncol. 2007,31:169–173.
[107] M. Endoh, G. Tamura, T. Honda, N. Homma, M. Terashima, S. Nishizuka, T. Motoyama, RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cance[J]r. Br. J. Cancer. 2005,93:1395–1399.
[108] Z. Zhang, D. Sun, N. Van do, A. Tang, L. Hu, G. Huang. Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma[J]. Int. J. Cancer. 2007,120:32–38.
[109] E.T. Sakamoto-Hojo, S.S. Mello, E. Pereira, A.L. Fachin, R.S. Cardoso, C.M. Junta, P. Sandrin-Garcia, E.A. Donadi, G.A. Passos, Gene expression profiles in human cells submitted to genotoxic stress[J]. Mutat. Res. 2003,544:403–413.
[110] Glantschnig H, Rodan GA, Reszka AA. Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. J Biol Chem 2002;277:42987–42996.
[111] K. Akino, M. Toyota, H. Suzuki, H. Mita, Y. Sasaki, M. Ohe-Toyota, J.P.Issa, Y. Hinoda, K. Imai, T. Tokino. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer[ J ]. Gastroenterology 129(2005) 156–169.
[112] Ait-Si-Ali S. Carlisi D, Ramirez S, Upegui-Gonzalez LC, Duquet A, Robin P, Rudkin B, Harel-Bellan A,Trouche D. Phosphorylation by p44 MAP kinase/ERK1 stimulates CBP histone acetyl transferase activity in vitro[ J ]. Biochem. Biophys. Res. Commun. 1999, 262: 157–162.
[113] Huang W C, Chen C C. Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity[ J ]. Mol Cell Biol. 2005 ,25:6592-602.
[114] Yuan, LW, and Gambee JE. Phosphorylation of p300 at serine 89 by protein kinase C[ J ]. J. Biol. Chem.2000, 275: 40946–40951.
[115] Missero C, Calautti E, Eckner R, Chin J, Tsai LH, Livingston DM, Dotto GP. Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation[ J ]. Proc Natl Acad Sci USA. 1995, 92: 5451-5455.
[116] Wang X, Pan L, Feng Y, Wang Y, Han Q, Han S, Guo J, Huang B, Lu J. p300 plays a role in p16(INK4a) expression and cell cycle arrest[ J ]. Oncogene. 2007, Oct 1: 1–11.
[117] Akina K, Toyota M, Suzuki H, Mita H, Sasaki Y, Ohe-Toyota M, Issa JP, Hinoda Y, Imai K, Tokino T. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer[ J ]. Gastroenterology. 2005, 129: 156-169.