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The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, Maryland 21231
Much excitement has recently been generated by the discovery of the Smad genes, encoding proteins that transduce signals from the transforming growth factor ß family of cytokines. Here, we report the completion of cloning of the six known human Smads, providing novel sequences for Smad5 and Smad6. Previously, Smad4 and Smad2 were shown to be mutated in human cancers. However, analysis of the other four Smad genes revealed no mutations in a total of 167 tumors, including those from colon, breast, lung, and pancreas. These results suggest that the various Smad genes have different functions and demonstrate that mutations in these four genes do not, in general, account for the widespread resistance to transforming growth factor ß that is found in human tumors.
1 This work was supported by NIH Grants CA43460 and CA57345. B. V. is an Investigator of the Howard Hughes Research Institute.
2 To whom requests for reprints should be addressed.
Received 3/14/97. Accepted 5/ 9/97.
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S. Zhou, P. Buckhaults, L. Zawel, F. Bunz, G. Riggins, J. Le Dai, S. E. Kern, K. W. Kinzler, and B. Vogelstein Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells PNAS, March 3, 1998; 95(5): 2412 - 2416. [Abstract] [Full Text] [PDF]
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A. Hata, G. Lagna, J. Massagué, and A. Hemmati-Brivanlou Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor Genes & Dev., January 15, 1998; 12(2): 186 - 197. [Abstract] [Full Text]
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T. Quan, T. He, J. J. Voorhees, and G. J. Fisher Ultraviolet Irradiation Blocks Cellular Responses to Transforming Growth Factor-beta by Down-regulating Its Type-II Receptor and Inducing Smad7 J. Biol. Chem., July 6, 2001; 276(28): 26349 - 26356. [Abstract] [Full Text] [PDF]
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H. Yamada, K. Vijayachandra, C. Penner, and A. Glick Increased Sensitivity of Transforming Growth Factor (TGF) beta 1 Null Cells to Alkylating Agents Reveals a Novel Link between TGFbeta Signaling and O6-Methylguanine Methyltransferase Promoter Hypermethylation J. Biol. Chem., May 25, 2001; 276(22): 19052 - 19058. [Abstract] [Full Text] [PDF]
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E. Piek, W. J. Ju, J. Heyer, D. Escalante-Alcalde, C. L. Stewart, M. Weinstein, C. Deng, R. Kucherlapati, E. P. Bottinger, and A. B. Roberts Functional Characterization of Transforming Growth Factor beta Signaling in Smad2- and Smad3-deficient Fibroblasts J. Biol. Chem., June 1, 2001; 276(23): 19945 - 19953. [Abstract] [Full Text] [PDF]
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