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Transforming Growth Factor-ß1 Mediates Cellular Response to DNA Damage in Situ¹

Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720 [K. B. E., R. L. H-P., S. A. R., M. J. P., M. H. B-H.]; Division of Medical Oncology, Vanderbilt University, Nashville, Tennessee 37235 [C. A.]; Department of Radiology, University of Utah Medical Center, Salt Lake City, Utah 84112 [R. W.]; and Mt. Zion Cancer Research Institute, University of California at San Francisco, San Francisco, California 94143-0875 [R. J. A.]

Transforming growth factor (TGF)-ß1 is rapidly activated after ionizing radiation, but its specific role in cellular responses to DNA damage is not known. Here we use Tgfß1 knockout mice to show that radiation-induced apoptotic response is TGF-ß1 dependent in the mammary epithelium, and that both apoptosis and inhibition of proliferation in response to DNA damage decrease as a function of TGF-ß1 gene dose in embryonic epithelial tissues. Because apoptosis in these tissues has been shown previously to be p53 dependent, we then examined p53 protein activation. TGF-ß1 depletion, by either gene knockout or by using TGF-ß neutralizing antibodies, resulted in decreased p53 Ser-18 phosphorylation in irradiated mammary gland. These data indicate that TGF-ß1 is essential for rapid p53-mediated cellular responses that mediate cell fate decisions in situ.

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