Abstract
The c-ski proto-oncogene product (c-Ski) acts as a co-repressor and binds to other co-repressors N-CoR/SMRT and mSin3A which form a complex with histone deacetylase (HDAC). c-Ski mediates the transcriptional repression by a number of repressors, including nuclear hormone receptors and Mad. c-Ski also directly binds to, and recruits the HDAC complex to Smads, leading to inhibition of tumor growth factor-β (TGF-β) signaling. This is consistent with the function of ski as an oncogene. Here we show that loss of one copy of c-ski increases susceptibility to tumorigenesis in mice. When challenged with a chemical carcinogen, c-ski heterozygous mice showed an increased level of tumor formation relative to wild-type mice. In addition, c-ski-deficient mouse embryonic fibroblasts (MEFs) had increased proliferative capacity, whereas overexpression of c-Ski suppressed the proliferation. Furthermore, the introduction of activated Ki-ras into c-ski-deficient MEFs resulted in neoplastic transformation. These findings demonstrate that c-ski acts as a tumor suppressor in some types of cells. The level of cdc25A mRNA, which is down regulated by two tumor suppressor gene products, Rb and Mad, was upregulated in c-ski-deficient MEFs, whereas it decreased by overexpressing c-Ski in MEFs. This is consistent with the fact that c-Ski acts as a co-repressor of Mad and Rb. These results support the view that the decreased activities of Mad and Rb in ski-deficient cells at least partly contribute to enhanced proliferation and susceptibility to tumorigenesis. Human c-ski gene was mapped to a region close to the p73 tumor suppressor gene at the 1p36.3 locus, which is already known to contain multiple uncharacterized tumor suppressor genes.
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Abbreviations
- c-ski:
-
cellular ski proto-oncogene
- c-Ski:
-
c-ski gene product
- DMBA:
-
9,10-dimethyl-1,2-benzanthracene
- HDAC:
-
histone deacetylase
- MEFs:
-
mouse embryonic fibroblasts
- TGF-β:
-
tumor growth factor-β
References
Akiyoshi S, Inoue H, Hanai J, Kusanagi K, Nemoto N, Miyazono K, Kawabata M . 1999 J. Biol. Chem. 274: 35269–35277
Alland L, Muhle R, Hou Jr H, Potes J, Chin L, Screiber-Agus N, DePinho RA . 1997 Nature 387: 49–55
Ayer DE, Eisenman RN . 1993 Genes Dev. 7: 2110–2119
Ayer DE, Kretzner L, Eisenman RN . 1993 Cell 72: 211–222
Ayer DE, Lawrence QA, Eisenman RN . 1995 Cell 80: 767–776
Berk M, Desai SY, Heyman HC, Colmenares C . 1997 Genes Dev. 11: 2029–2039
Boyer PL, Colmenares C, Stavnezer E, Hughes SH . 1993 Oncogene 8: 457–466
Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T . 1998 Nature 391: 597–601
Chen JD, Evans RM . 1995 Nature 377: 454–457
Cheng NC, Van Roy N, Chan A, Beitsma M, Westerveld A, Speleman F, Versteeg R . 1995 Oncogene 10: 291–297
Chin L, Schreiber-Agus N, Pellicer I, Chen K, Lee H-W, Dudast M, Cordon-Cardo C, Depinho RA . 1995 Proc. Natl. Acad. Sci. USA 92: 8488–8492
Colmenares C, Stavnezer E . 1989 Cell 59: 293–303
Colmenares C, Teumer JK, Stavnezer E . 1991 Mol. Cell. Biol. 11: 1167–1170
Dahl R, Kieslinger M, Beug H, Hayman MJ . 1998 Proc. Natl. Acad. Sci. USA 95: 11187–11192
Doucas V, Evans RM . 1996 Biochim. Biophys. Acta. 1288: 25–29
Field SJ, Tsai F-Y, Kuo F, Zubiaga AM, Kaelin Jr WG, Livingston DM, Orkin SH, Greenberg ME . 1996 Cell 85: 549–561
Galaktionov K, Chen X, Beach D . 1996 Nature 382: 511–517
Goodrich DW, Lee WH . 1992 Nature 360: 177–179
Grandori C, Eisenman RN . 1997 Trends Biochem. Sci. 22: 177–181
Hannon GJ, Beach D . 1994 Nature 371: 257–261
Hassing CA, Fleischer TC, Billin AN, Schreiber SL, Ayer DE . 1997 Cell 89: 341–347
Heinzel T, Lavinsky RM, Mullen T-M, Söderström M, Laherty CD, Torchia J, Yang W-M, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG . 1997 Nature 387: 43–48
Heyman HC, Stavnezer E . 1994 J. Biol. Chem. 269: 26996–27003
Hörlein AJ, Näär AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Söderström M, Glass CK, Rosenfeld MG . 1995 Nature 377: 397–404
Ichimiya S, Nimura Y, Kageyama H, Takada N, Sunahara M, Shishikura T, Nakamura Y, Sakiyama S, Seki N, Ohira M, Kaneko Y, McKeon F, Caput D, Nakagawara A . 1999 Oncogene 18: 1061–1066
Imyanitov EN, Birrell GW, Filippovich I, Sorokina N, Arnold J, Mould MA, Wright K, Walsh M, Mok SC, Lavin MF, Chenevix-Trench G, Khanna KK . 1999 Oncogene 18: 4640–4642
Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F, Caput D . 1997 Cell 90: 809–819
Kokura K, Kaul SC, Wadhwa R, Nomura T, Khan MM, Shinagawa T, Yasukawa T, Colmanares C, Ishii S . 2001 J. Biol. Chem. 276: 34115–34121
Knudson Jr AG . 1971 Proc. Natl. Acad. Sci. USA 68: 820–823
Knudson Jr AG . 1997 Ann. NY Acad. Sci. USA 833: 58–67
Kruzelock RP, Murphy EC, Strong LC, Naylor SL, Hansen MF . 1997 Cancer Res. 57: 106–109
Laherty CD, Yang W-M, Sun J-M, Davie JR, Seto E, Eisenman RN . 1997 Cell 89: 349–356
Lawrence JB, Singer RH, McNeil JA . 1990 Science 249: 928–932
Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR . 1997 Nature 387: 422–426
Li Y, Turck CM, Teumer JK, Stavnezer E . 1986 J. Virol. 57: 1065–1072
Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q . 1999 Genes Dev. 13: 2196–2206
Luo RX, Postigo AA, Dean DC . 1998 Cell 92: 463–473
Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, Troalen F, Trouche D, Harel-Bellan A . 1998 Nature 391: 601–605
Martinsson T, Sjoberg RM, Hedborg F, Kogner P . 1995 Cancer Res. 55: 5681–5686
Massagué J, Wotton D . 2000 EMBO J. 19: 1745–1754
Mori N, Morosetti R, Spira S, Lee S, Ben-Yehuda D, Schiller G, Landolfi R, Mizoguchi H, Koeffler HP . 1998 Blood 92: 3405–3409
Muller H, Helin K . 2000 Biochem. Biophys. Acta. 1470: M1–M12
Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine AJ, George DL . 1999 Genes Dev. 13: 2490–2501
Nagase T, Mizuguchi G, Nomura N, Ishizaki R, Ueno Y, Ishii S . 1990 Nucleic Acids Res. 18: 337–343
Nagase T, Nomura N, Ishii S . 1993 J. Biol. Chem. 268: 13710–13716
Nagy L, Kao H-Y, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Screiber SL, Evans RM . 1997 Cell 89: 373–380
Neufeld TP, de la Cruz AF, Johnston LA, Edgar BA . 1998 Cell 93: 1183–1193
Nevins JR . 1992 Science 258: 424–429
Nicol R, Stavnezer E . 1998 J. Biol. Chem. 273: 3588–3597
Nomura T, Khan MM, Kaul SC, Dong H-D, Wadhwa R, Colmenares C, Kohno I, Ishii S . 1999 Genes Dev. 13: 412–423
Nomura N, Sasamoto S, Ishii S, Date T, Matsui M, Ishizaki R . 1989 Nucleic Acids Res. 17: 5489–5500
Pear WS, Nolan GP, Scott ML, Baltimore D . 1993 Proc. Natl. Acad. Sci. USA 90: 8392–8396
Pearson-White S, Deacon D, Crittenden R, Brady G, Iscove N, Quesenberry PJ . 1995 Blood 86: 2146–2155
Persons DA, Allay JA, Allay ER, Smeyne RJ, Ashmun RA, Sorrentino BP, Nienhuis AW . 1997 Blood 90: 1777–1786
Roussel MF, Ashmun RA, Sher CJ, Eisenman RN, Ayer DE . 1996 Mol. Cell. Biol. 16: 2796–2801
Schreiber-Agus N, Meng Y, Hoang T, Hou Jr H, Chen K, Greenberg R, Cordon-Cardo C, Lee H-W, DePinho RA . 1998 Nature 393: 483–487
Shinagawa T, Dong H-D, Xu M, Maekawa T, Ishii S . 2000 EMBO J. 19: 2280–2291
Sleeman JP, Laskey RA . 1993 Oncogene 8: 67–77
Stavnezer E, Brodeur D, Brennan L . 1989 Mol. Cell. Biol. 9: 4038–4045
Sun Y, Liu X, Eaton EN, Lane WS, Lodish HF, Weinberg RA . 1999 Mol. Cell 4: 499–509
Sutrave P, Copeland TD, Showalter SD, Hughes SH . 1990a Mol. Cell. Biol. 10: 3137–3144
Sutrave P, Hughes SH . 1989 Mol. Cell. Biol. 9: 4046–4051
Sutrave P, Kelly AM, Hughes SH . 1990b Genes Dev. 4: 1462–1472
Tokitou F, Nomura T, Khan MM, Kaul SC, Wadhwa R, Yasukawa T, Kohno I, Ishii S . 1999 J. Biol. Chem. 274: 4485–4488
van den Engh G, Sachs R, Trask BJ . 1992 Science 257: 1410–1412
Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, Grosveld F, Pandolfi PP . 1998 Science 279: 1547–1551
Weinberg RA . 1995 Cell 81: 323–330
Xu W, Angelis K, Danielpour D, Haddad MM, Bischof O, Campisi J, Stavnezer E, Medrano EE . 2000 Proc. Natl. Acad. Sci. USA 97: 5924–5929
Yamasaki L, Jacks T, Bronson R, Goillot E, Harlow E, Dyson NJ . 1996 Cell 85: 537–548
Zhang HS, Postigo AA, Dean DC . 1999 Cell 97: 53–61
Acknowledgements
We are grateful to N Nomura for advice on mapping, M Noda for the kind gift of MuLV, and E Stavnezer for helpful discussions. This work was supported in part by grant HD30728 from the National Institutes of Health to C Colmenares.
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Shinagawa, T., Nomura, T., Colmenares, C. et al. Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice. Oncogene 20, 8100–8108 (2001). https://doi.org/10.1038/sj.onc.1204987
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DOI: https://doi.org/10.1038/sj.onc.1204987
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