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Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53

Oncogene volume 25, pages 359–369 (2006)Cite this article

Abstract

Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the MSP (MST-1/HGFL) gene, encoding the ligand of the receptor tyrosine kinase RON, implicated in a variety of cellular responses. Mutant p53 associates with the MSP gene promoter and represses its transcriptional activity, leading to a decrease in mRNA levels and a subsequent decrease in the levels of secreted MSP protein. Forced downregulation of MSP expression in H1299 cells, derived from a large-cell lung carcinoma, confers increased resistance against etoposide-induced cell death. These antiapoptotic consequences of MSP downregulation seemingly conflict with the well-documented ability of the RON receptor to promote cell survival and tumor progression when aberrantly hyperactive. Yet, they are consistent with the fact that reduced MSP expression was observed in many types of human cancer, including large-cell lung carcinoma. Thus, repression of MSP gene expression by mutant p53 may contribute to oncogenesis in a cell type-specific manner.

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References

  • Albor A, Kaku S, Kulesz-Martin M . (1998). Cancer Res 58: 2091–2094.

  • Bardella C, Costa B, Maggiora P, Patane S, Olivero M, Ranzani GN et al. (2004). Cancer Res 64: 5154–5161.

  • Bargonetti J, Manfredi JJ . (2002). Curr Opin Oncol 14: 86–91.

  • Bezerra JA, Carrick TL, Degen JL, Witte D, Degen SJ . (1998). J Clin Invest 101: 1175–1183.

  • Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P et al. (2001). Proc Natl Acad Sci USA 98: 13790–13795.

  • Blagosklonny MV . (2000). FASEB J 14: 1901–1907.

  • Blandino G, Levine AJ, Oren M . (1999). Oncogene 18: 477–485.

  • Brummelkamp TR, Bernards R, Agami R . (2002). Science 296: 550–553.

  • Cadwell C, Zambetti GP . (2001). Gene 277: 15–30.

  • Camp ER, Liu W, Fan F, Yang A, Somcio R, Ellis LM . (2005). Ann Surg Oncol 12: 273–281.

  • Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J et al. (2002a). Mol Biol Cell 13: 1929–1939.

  • Chen YQ, Zhou YQ, Fu LH, Wang D, Wang MH . (2002b). Carcinogenesis 23: 1811–1819.

  • Chin KV, Ueda K, Pastan I, Gottesman MM . (1992). Science 255: 459–462.

  • Correll PH, Iwama A, Tondat S, Mayrhofer G, Suda T, Bernstein A . (1997). Genes Funct 1: 69–83.

  • Danilkovitch-Miagkova A, Leonard EJ . (2001). Apoptosis 6: 183–190.

  • Demidenko ZN, Fojo T, Blagosklonny MV . (2005). FEBS Lett 579: 2231–2235.

  • Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K et al. (2001). Nature 412: 822–826.

  • Dippold W . (1993). Z Gastroenterol 31: 24–27.

  • el-Deiry WS . (1998). Semin Cancer Biol 8: 345–357.

  • Frazier MW, He X, Wang J, Gu Z, Cleveland JL, Zambetti GP . (1998). Mol Cell Biol 18: 3735–3743.

  • Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M et al. (2001). Proc Natl Acad Sci USA 98: 13784–13789.

  • Gohler T, Jager S, Warnecke G, Yasuda H, Kim E, Deppert W . (2005). Nucleic Acids Res 33: 1087–1100.

  • Gualberto A, Aldape K, Kozakiewicz K, Tlsty TD . (1998). Proc Natl Acad Sci USA 95: 5166–5171.

  • Gurova KV, Rokhlin OW, Budanov AV, Burdelya LG, Chumakov PM, Cohen MB et al. (2003). Cancer Res 63: 2905–2912.

  • Halevy O, Michalovitz D, Oren M . (1990). Science 250: 113–116.

  • Harbour JW, Dean DC . (2000). Genes Dev 14: 2393–2409.

  • Higgins JP, Shinghal R, Gill H, Reese JH, Terris M, Cohen RJ et al. (2003). Am J Pathol 162: 925–932.

  • Hinds PW, Finlay CA, Quartin RS, Baker SJ, Fearon ER, Vogelstein B, Levine AJ . (1990). Cell Growth Differ 1: 571–580.

  • Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M . (2002). J Biol Chem 277: 3247–3257.

  • Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C et al. (2003). Am J Pathol 162: 1151–1162.

  • Iwama A, Yamaguchi N, Suda T . (1996). EMBO J 15: 5866–5875.

  • Kim E, Deppert W . (2004). J Cell Biochem 93: 878–886.

  • Li R, Sutphin PD, Schwartz D, Matas D, Almog N, Wolkowicz R et al. (1998). Oncogene 16: 3269–3277.

  • Lotem J, Sachs L . (1995). Proc Natl Acad Sci USA 92: 9672–9676.

  • Matas D, Sigal A, Stambolsky P, Milyavsky M, Weisz L, Schwartz D et al. (2001). EMBO J 20: 4163–4172.

  • Miller AD, Van Hoeven NS, Liu SL . (2004). BMC Cancer 4: 64.

  • Muraoka RS, Sun WY, Colbert MC, Waltz SE, Witte DP, Degen JL et al. (1999). J Clin Invest 103: 1277–1285.

  • Murphy KL, Dennis AP, Rosen JM . (2000). FASEB J 14: 2291–2302.

  • O'Farrell TJ, Ghosh P, Dobashi N, Sasaki CY, Longo DL . (2004). Cancer Res 64: 8199–8207.

  • Oren M . (2003). Cell Death Differ 10: 431–442.

  • Peace BE, Hughes MJ, Degen SJ, Waltz SE . (2001). Oncogene 20: 6142–6151.

  • Ramaswamy S, Tamayo P, Rifkin R, Mukherjee S, Yeang CH, Angelo M et al. (2001). Proc Natl Acad Sci USA 98: 15149–15154.

  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. (2004). Neoplasia 6: 1–6.

  • Sakamoto O, Iwama A, Amitani R, Takehara T, Yamaguchi N, Yamamoto T et al. (1997). J Clin Invest 99: 701–709.

  • Sampath J, Sun D, Kidd VJ, Grenet J, Gandhi A, Shapiro LH et al. (2001). J Biol Chem 276: 39359–39367.

  • Scian MJ, Stagliano KE, Deb D, Ellis MA, Carchman EH, Das A et al. (2004a). Oncogene 23: 4430–4443.

  • Scian MJ, Stagliano KE, Ellis MA, Hassan S, Bowman M, Miles MF et al. (2004b). Cancer Res 64: 7447–7454.

  • Serrano M . (2000). Carcinogenesis 21: 865–869.

  • Sigal A, Rotter V . (2000). Cancer Res 60: 6788–6793.

  • Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al. (2001). Proc Natl Acad Sci USA 98: 10869–10874.

  • Soussi T . (2000). Ann NY Acad Sci 910: 121–137; discussion 137–139.

  • Storz MN, van de Rijn M, Kim YH, Mraz-Gernhard S, Hoppe RT, Kohler S . (2003). J Invest Dermatol 120: 865–870.

  • Vogelstein B, Lane D, Levine AJ . (2000). Nature 408: 307–310.

  • Vousden KH, Lu X . (2002). Nat Rev Cancer 2: 594–604.

  • Wang D, Shen Q, Chen YQ, Wang MH . (2004). Oncogene 23: 1668–1680.

  • Wang D, Shen Q, Xu XM, Chen YQ, Wang MH . (2005). Carcinogenesis 26: 27–36.

  • Wang MH, Wang D, Chen YQ . (2003). Carcinogenesis 24: 1291–1300.

  • Wang MH, Yoshimura T, Skeel A, Leonard EJ . (1994). J Biol Chem 269: 3436–3440.

  • Weinmann AS, Farnham PJ . (2002). Methods 26: 37–47.

  • Weisz L, Zalcenstein A, Stambolsky P, Cohen Y, Goldfinger N, Oren M et al. (2004). Cancer Res 64: 8318–8327.

  • Willett CG, Wang MH, Emanuel RL, Graham SA, Smith DI, Shridhar V et al. (1998). Am J Respir Cell Mol Biol 18: 489–496.

  • Wolf D, Harris N, Rotter V . (1984). Cell 38: 119–126.

  • Yang X, Pater A, Tang SC . (1999). Oncogene 18: 4546–4553.

  • Zalcenstein A, Stambolsky P, Weisz L, Muller M, Wallach D, Goncharov TM et al. (2003). Oncogene 22: 5667–5676.

  • Zastawny RL, Salvino R, Chen J, Benchimol S, Ling V . (1993). Oncogene 8: 1529–1535.

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Acknowledgements

We thank R Agami and W Kaelin for the generous gift of pSuper and pCMV-neo-Bam p53R175H expression plasmids, respectively. This research was supported by a Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI), EC FP6 funding (Contract 502983), Grant R37 CA40099 from the National Cancer Institute, and Yad Abraham Center for Cancer Diagnosis and Therapy. This publication reflects the authors' views and not necessarily those of the European Community. The European Community is not liable for any use that may be made of the information contained herein. VR is the incumbent of the Norman and Helen Asher Professorial Chair Cancer Research at the Weizmann Institute.

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  1. A Zalcenstein and L Weisz: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    A Zalcenstein, L Weisz, P Stambolsky, J Bar, V Rotter & M Oren

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  1. A Zalcenstein
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Correspondence to M Oren.

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Zalcenstein, A., Weisz, L., Stambolsky, P. et al. Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53. Oncogene 25, 359–369 (2006). https://doi.org/10.1038/sj.onc.1209061

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