Abstract
The Smad family proteins are critical components of the transforming growth factor (TGF)-β signaling pathway. TGF-β is a multipotent cytokine that elicits many biological functions. In particular, TGF-β exhibits effects on the cell cycle manifested by G1-phase arrest, differentiation, or apoptosis of several target cells, suggesting that disruption of TGF-β signaling pathway could be involved in cancer formation. Here we show one missense mutation of the Smad4 gene in the MH1 domain (P102L) and one frame shift mutation resulting in termination in the MH2 domain (Δ(483–552)) in acute myelogeneous leukemia. Both of the mutated Smad4 proteins lack transcriptional activities. Concomitant expression of the P102L mutant with wild-type Smad4 inactivates wild-type Smad4 through inhibiting its DNA-binding ability. The Δ(483–552) mutant blocks nuclear translocation of wild-type Smad4 and thus disrupts TGF-β signaling. This is the first report showing that mutations in the Smad4 gene are associated with the pathogenesis of acute myelogeneous leukemia and the obtained results should provide useful insights into the mechanism whereby disruption of TGF-β signaling pathway could lead to acute myelogeneous leukemia.
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References
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR and Sultan C. . 1991 Br. J. Haematol. 78: 325–329.
de Winter JP, Roelen BA, ten Dijke P, van der Burg B and van den Eijnden-van Raaij AJ. . 1997 Oncogene 14: 1891–1899.
Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier JM. . 1998 EMBO J. 17: 3091–3100.
Drexler HG, Gaedicke G, Maeda S, Chen PM and Minowada J. . 1986 Tumour Biol. 6: 503–517.
Feng XH, Zhang Y, Wu RY and Derynck R. . 1998 Genes Dev. 12: 2153–2163.
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH and Kern SE. . 1996 Science 271: 350–353.
Hangaishi A, Ogawa S, Imamura N, Miyawaki S, Miura Y, Uike N, Shimazaki C, Emi N, Takeyama K, Hirosawa S, Kamada N, Kobayashi Y, Takemoto Y, Kitani T, Toyama K, Ohtake S, Yazaki Y, Ueda R and Hirai H. . 1996 Blood 87: 4949–4958.
Heldin CH, Miyazono K and ten Dijke P. . 1997 Nature 390: 465–471.
Hua X, Liu X, Ansari DO and Lodish HF. . 1998 Genes Dev. 12: 3084–3095.
Imai Y, Kurokawa M, Tanaka K, Friedman AD, Ogawa S, Mitani K, Yazaki Y and Hirai H. . 1998 Biochem. Biophys. Res. Commun. 252: 582–589.
Jonk LJ, Itoh S, Heldin CH, ten Dijke P and Kruijer W. . 1998 J. Biol. Chem. 273: 21145–21152.
Kaneko H, Horiike S, Sasai Y, Iwai T, Nakao M, Yokota S, Taniwaki M, Kashima K and Misawa S. . 1998 Acta Haematol. 99: 187–190.
Kawabata M, Inoue H, Hanyu A, Imamura T and Miyazono K. . 1998 EMBO J. 17: 4056–4065.
Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki Y and Hirai H. . 1998a Blood 92: 4003–4012.
Kurokawa M, Mitani K, Irie K, Matsuyama T, Takahashi T, Chiba S, Yazaki Y, Matsumoto K and Hirai H. . 1998b Nature 394: 92–96.
Lagna G, Hata A, Hemmati-Brivanlou A and Massague J. . 1996 Nature 383: 832–836.
Le Dai J, Turnacioglu KK, Schutte M, Sugar AY and Kern SE. . 1998 Cancer Res. 58: 4592–4597.
Liu F, Pouponnot C and Massague J. . 1997 Genes Dev. 11: 3157–3167.
Liu YC, Kawagishi M, Mikayama T, Inagaki Y, Takeuchi T and Ohashi H. . 1993 Proc. Natl. Acad. Sci. USA 90: 8957–8961.
Massague J. . 1998 Annu. Rev. Biochem. 67: 753–791.
Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K and ten Dijke P. . 1997 EMBO J. 16: 5353–5362.
Ogawa S, Hirano N, Sato N, Takahashi T, Hangaishi A, Tanaka K, Kurokawa M, Tanaka T, Mitani K, Yazaki Y and Hirai H. . 1994 Blood 84: 2431–2435.
Ohta M, Greenberger JS, Anklesaria P, Bassols A and Massague J. . 1987 Nature 329: 539–541.
Piacibello W, Severino A, Stacchini A and Aglietta M. . 1991 Haematologica 76: 460–466.
Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero Jr RA, Meltzer PS, Hahn SA and Kern SE. . 1996 Cancer Res. 56: 2527–2530.
Shi Y, Hata A, Lo RS, Massague J and Pavletich NP. . 1997 Nature 388: 87–93.
Stroschein SL, Wang W and Luo K. . 1999 J. Biol. Chem. 274: 9431–9441.
Tanaka T, Mitani K, Kurokawa M, Ogawa S, Tanaka K, Nishida J, Yazaki Y, Shibata Y and Hirai H. . 1995a Mol. Cell. Biol. 15: 2383–2392.
Tanaka T, Nishida J, Mitani K, Ogawa S, Yazaki Y and Hirai H. . 1994 J. Biol. Chem. 269: 24020–24026.
Tanaka T, Tanaka K, Ogawa S, Kurokawa M, Mitani K, Nishida J, Shibata Y, Yazaki Y and Hirai H. . 1995b EMBO J. 14: 341–350.
Wrana JL, Attisano L, Wieser R, Ventura F and Massague J. . 1994 Nature 370: 341–347.
Wu RY, Zhang Y, Feng XH and Derynck R. . 1997 Mol. Cell. Biol. 17: 2521–2528.
Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B and Kern SE. . 1998 Mol. Cell 1: 611–617.
Zhang Y and Derynck R. . 1999 Trends Cell Biol. 9: 274–279.
Zhang Y, Feng X, We R and Derynck R. . 1996 Nature 383: 168–172.
Zhang Y, Feng XH and Derynck R. . 1998 Nature 394: 909–913.
Zhang Y, Musci T and Derynck R. . 1997 Curr. Biol. 7: 270–276.
Zhou S, Buckhaults P, Zawel L, Bunz F, Riggins G, Le Dai J, Kern SE, Kinzler KW and Vogelstein B. . 1998 Proc. Natl. Acad. Sci. USA 95: 2412–2416.
Acknowledgements
This work was supported in part by The Mitsubishi Foundation and Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Culture of Japan.
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Imai, Y., Kurokawa, M., Izutsu, K. et al. Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis. Oncogene 20, 88–96 (2001). https://doi.org/10.1038/sj.onc.1204057
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DOI: https://doi.org/10.1038/sj.onc.1204057
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