BAG-1 haplo-insufficiency impairs lung tumorigenesis
详细信息 查看全文
- 作者：Rudolf G?tz (1)
Boris W Kramer (2)
Guadalupe Camarero (1)
Ulf R Rapp (1) - 刊名：BMC Cancer
- 出版年：2004
- 出版时间：December 2004
- 年：2004
- 卷：4
- 期：1
- 全文大小：1049KB
- 参考文献：1. Takayama S, Sato T, Krajewski S, Kochel K, Irie S, Millan JA, Reed JC: Cloning and functional analysis of BAG-1: A novel Bcl-2- binding protein with anti-cell death activity. / Cell 1995, 80: 279-84. CrossRef
2. Wang HG, Takayama S, Rapp UR, Reed JC: Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. / Proc Natl Acad Sci USA 1996, 93: 7063-068. CrossRef
3. Townsend PA, Cutress RI, Sharp A, Brimmell M, Packham G: BAG-1: a multifunctional regulator of cell growth and survival. / Biochim Biophys Acta 2003, 1603: 83-8.
4. Mayer MP, Brehmer D, Gassler CS, Bukau B: Hsp70 chaperone machines. / Adv Protein Chem 2001, 59: 1-4. CrossRef
5. Weinstein IB: Cancer. Addiction to oncogenes--the Achilles heal of cancer. / Science 2002, 297: 63-4. CrossRef
6. Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, Zhang XF: Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. / Recent Prog Horm Res 2001, 56: 127-55. CrossRef
7. Wang HG, Rapp UR, Reed JC: Bcl-2 targets the protein kinase Raf-1 to mitochondria. / Cell 1996, 87: 629-38. CrossRef
8. Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA: Role of Raf in vascular protection from distinct apoptotic stimuli. / Science 2003, 301: 94-6. CrossRef
9. Jr JT, McCubrey JA: Targeting the Raf kinase cascade in cancer therapy - novel molecular targets and therapeutic strategies. / Expert Opin Ther Targets 2002, 6: 659-78. CrossRef
10. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA: Mutations of the BRAF gene in human cancer. / Nature (London) 2002, 417: 949-54. CrossRef
11. Cutress RI, Townsend PA, Brimmell M, Bateman AC, Hague A, Packham G: BAG-1 expression and function in human cancer. / Br J Cancer 2002, 87: 834-39. CrossRef
12. Tybulewicz VLJ, Crawford CE, Jackson PK, Bronson RT, Mulligan RC: Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. / Cell 1991, 65: 1153-163. CrossRef
13. Kramer BW, G?tz R, Rapp UR: Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure. / BMC Cancer 2004, 4: 24. CrossRef
14. Kerkhoff E, Fedorov LM, Siefken R, Walter AO, Papadopoulus T, Rapp UR: Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-type protein. / Cell Growth Diff 2000, 11: 185-90.
15. Takayama S, Reed JC, Homma S: Heat-shock proteins as regulators of apoptosis. / Oncogene 2003, 22: 9041-047. CrossRef
16. Townsend PA, Cutress RI, Carroll CJ, Lawrence KM, Scarabelli TM, Packham G, Stephanou A, Latchman DS: BAG-1 proteins protect cardiac myocytes from simulated ischemia/reperfusion-induced apoptosis via an alternate mechanism of cell survival independent of the proteasome. / J Biol Chem 2004, 279: 20723-0728. CrossRef
17. Rapp UR, Rennefahrt U, Troppmair J: Bcl-2 proteins: master switches at the intersection of death signaling and the survival control by Raf kinases. / Biochim Biophys Acta 2004, 1644: 149-58. CrossRef
18. Briknarova K, Takayama S, Brive L, Havert ML, Knee DA, Velasco J, Homma S, Cabezas E, Stuart J, Hoyt DW, Satterthwait AC, Llinas M, Reed JC, Ely KR: Structural analysis of BAG1 cochaperone and its interactions with Hsc70 heat shock protein. / Nat Struct Biol 2001, 8: 349-52. CrossRef
19. Sondermann H, Scheufler C, Schneider C, H?hfeld J, Hartl FU, Moarefi I: Structure of a Bag/Hsc70 complex: Convergent functional evolution of Hsp70 nucleotide exchange factors. / Science 2001, 291: 1553-557. CrossRef
20. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/4/85/prepub - 作者单位：Rudolf G?tz (1)
Boris W Kramer (2)
Guadalupe Camarero (1)
Ulf R Rapp (1)
1. Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universit?t Würzburg, Versbacher Stra?e 5, D-97078, Würzburg, Germany
2. Universit?ts-Kinderklinik Würzburg, Josef-Schneider-Str. 2, D-97080, Würzburg, Germany - ISSN：1471-2407
文摘
Background BAG-1 is a multifunctional co-chaperone of heat shock proteins (Hsc70/Hsp70) that is expressed in most cells. It interacts with Bcl-2 and Raf indicating that it might connect protein folding with other signaling pathways. Evidence that BAG-1 expression is frequently altered in human cancers, in particular in breast cancer, relative to normal cells has been put forward but the notion that overexpression of BAG-1 contributes to poor prognosis in tumorigenesis remains controversial. Methods We have evaluated the effect of BAG-1 heterozygosity in mice in a model of non-small-cell lung tumorigenesis with histological and molecular methods. We have generated mice heterozygous for BAG-1, carrying a BAG-1 null allele, that in addition express oncogenic, constitutively active C-Raf kinase (SP-C C-Raf BxB) in type II pneumocytes. SP-C C-Raf BxB mice develop multifocal adenomas early in adulthood. Results We show that BAG-1 heterozygosity in mice impairs C-Raf oncogene-induced lung adenoma growth. Lung tumor initiation was reduced by half in BAG-1 heterozygous SP-C C-Raf BxB mice compared to their littermates. Tumor area was reduced by 75% in 4 month lungs of BAG-1 haploinsufficient mice compared to mice with two BAG-1 copies. Whereas BAG-1 heterozygosity did not affect the rate of cell proliferation or signaling through the mitogenic cascade in adenoma cells, it increased the rate of apoptosis. Conclusion Reduced BAG-1 expression specifically targets tumor cells to apoptosis and impairs tumorigenesis. Our data implicate BAG-1 as a key player in oncogenic transformation by Raf and identify it as a potential molecular target for cancer treatment.