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Cell Growth & Differentiation, Vol 6, Issue 6 623-629, Copyright © 1995 by American Association of Cancer Research


ARTICLES

Repression of Myc-Ras cotransformation by Mad is mediated by multiple protein-protein interactions

PJ Koskinen, DE Ayer and RN Eisenman
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.

Mad is a bHLH/Zip protein that, as a heterodimer with Max, can repress Myc-induced transcriptional transactivation. Expression of Mad is induced upon terminal differentiation of several cell types, where it has been postulated to down-regulate Myc-induced genes that drive cell proliferation. Here we show that Mad also blocks transformation of primary rat embryo fibroblasts by c-Myc and the activated c-Ha-Ras oncoproteins. Mad mutants lacking either the basic region, the leucine zipper, or an intact NH2-terminal protein interaction domain fail to inhibit Myc-Ras cotransformation. These results indicate that the repression of cotransformation requires DNA-binding and is mediated by multiple protein-protein interactions involving both Max and mSin3, a putative mammalian corepressor protein. With increasing amounts of the cotransfected myc gene, the numbers of transformed foci are reduced and the ability of Mad to inhibit focus formation is attenuated. Moreover, cell lines derived from such foci constitutively express both Myc and Mad proteins. Whereas Bcl-2 can significantly increase the numbers of transformed foci by enhancing the survival of myc-ras-transfected cells, it does not counteract the repressive effects of Mad on transformation, suggesting that Mad affects the growth properties rather than the viability of cells. Taken together, our results demonstrate that Mad is capable of antagonizing the biological effects of Myc and thereby suggest that Mad could function as a tumor suppressor gene.


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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1995 by the American Association of Cancer Research.