Transforming growth factor-beta1 mediates cellular response to DNA damage in situ.
Transforming growth factor (TGF)-beta1 is rapidly activated after ionizing radiation, but its specific role in cellular responses to DNA damage is not known. Here we use Tgfbeta1 knockout mice to show that radiation-induced apoptotic response is TGF-beta1 dependent in the mammary epithelium, and that both apoptosis and inhibition of proliferation in response to DNA damage decrease as a function of TGF-beta1 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-beta1 depletion, by either gene knockout or by using TGF-beta neutralizing antibodies, resulted in decreased p53 Ser-18 phosphorylation in irradiated mammary gland. These data indicate that TGF-beta1 is essential for rapid p53-mediated cellular responses that mediate cell fate decisions in situ.
Ewan
Kenneth B
KB
Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA.
Henshall-Powell
Rhonda L
RL
Ravani
Shraddha A
SA
Pajares
Maria Jose
MJ
Arteaga
Carlos
C
Warters
Ray
R
Akhurst
Rosemary J
RJ
Barcellos-Hoff
Mary Helen
MH
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology*; D004622:Embryo, Mammalian / Q000502:physiology / Q000528:radiation effects; D004847:Epithelial Cells / Q000502:physiology / Q000528:radiation effects; D005260:Female; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000528:radiation effects; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53