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Transforming growth factor-beta1 mediates cellular response to DNA damage in situ
Kenneth B Ewan1, Rhonda L Henshall-Powell, Shraddha A Ravani
1Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA.
Abstract:
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.
Insights
Transforming growth factor-beta1 (TGF-beta1) is crucial for the DNA damage response. This study shows TGF-beta1 is essential for radiation-induced apoptosis and p53 activation in mammary cells.
Area of Science:
- Cellular and Molecular Biology
- Radiation Oncology
- Cancer Research
Background:
- Ionizing radiation triggers rapid activation of transforming growth factor-beta1 (TGF-beta1).
- The precise role of TGF-beta1 in cellular responses to DNA damage remains unclear.
- TGF-beta1 signaling is implicated in various cellular processes, including apoptosis and proliferation.
Purpose of the Study:
- To elucidate the role of TGF-beta1 in radiation-induced cellular responses, specifically apoptosis and proliferation inhibition.
- To investigate the dependence of p53 activation on TGF-beta1 following DNA damage.
- To determine the impact of TGF-beta1 gene dose on cellular responses in embryonic epithelial tissues.
Main Methods:
- Utilized Tgfbeta1 knockout mice to assess the impact of TGF-beta1 deficiency on radiation responses.
- Examined apoptosis and proliferation inhibition in mammary epithelium and embryonic epithelial tissues after irradiation.
- Assessed p53 protein activation, specifically Ser-18 phosphorylation, in irradiated mammary glands under conditions of TGF-beta1 depletion.
Main Results:
- Radiation-induced apoptosis in the mammary epithelium is dependent on TGF-beta1.
- Both apoptosis and proliferation inhibition in response to DNA damage decrease with decreasing TGF-beta1 gene dose in embryonic epithelial tissues.
- TGF-beta1 depletion (via gene knockout or neutralizing antibodies) led to reduced p53 Ser-18 phosphorylation in irradiated mammary glands.
Conclusions:
- TGF-beta1 is essential for the rapid, p53-mediated cellular responses to DNA damage.
- TGF-beta1 plays a critical role in mediating cell fate decisions in situ following radiation exposure.
- The findings highlight TGF-beta1 as a key regulator of DNA damage response pathways.