TY - JOUR
T1 - Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence
AU - Tavana, Omid
AU - Benjamin, Cara L.
AU - Puebla-Osorio, Nahum
AU - Sang, Mei
AU - Ullrich, Stephen E.
AU - Ananthaswamy, Honnavara N.
AU - Zhu, Chengming
N1 - Funding Information:
The authors would like to thank Dr. G. Lozano for the p53P/P mouse, Dr. David L. Mitchell, for his help in analyzing the repair of UV-induced DNA lesions and Peter Wolf, M.D. for his assistance determining the skin fold thickness. Supported by the American Cancer Society-Bonnie Kies Foundation (to C.Z.) and Grants CA116933 (to C.Z.), CA 112660 and CA131207 (to S.E.U.) from the National Cancer Institute and Grant ES07784 from the National Institute of Environmental Health Sciences. C.L.B. is supported in part by Grant P50 CA093459 from the National Institutes of Health.
PY - 2010/8/15
Y1 - 2010/8/15
N2 - Genotoxic stress triggers the p53 tumor suppressor network to activate cellular responses that lead to cell cycle arrest, DNA repair, apoptosis or senescence. This network functions mainly through transactivation of different downstream targets, including cell cycle inhibitor p21, which is required for short-term cell cycle arrest or long-term cellular senescence, or proapoptotic genes such as p53 upregulated modulator of apoptosis (PUMA) and Noxa. However, the mechanism that switches from cell cycle arrest to apoptosis is still unknown. In this study, we found that mice harboring a hypomorphic mutant p53, R172P, a mutation that abrogates p53-mediated apoptosis while keeping cell cycle control mostly intact, are more susceptible to ultraviolet-B (UVB)-induced skin damage, inflammation and immunosuppression than wild-type mice. p53 R172P embryonic fibroblasts (MEFs) are hypersensitive to UVB and prematurely senesce after UVB exposure, in stark contrast to wild-type MEFs, which undergo apoptosis. However, these mutant cells are able to repair UV-induced DNA lesions, indicating that the UV hypersensitive phenotype results from the subsequent damage response. Mutant MEFs show an induction of p53 and p21 after UVR, while wild-type MEFs additionally induce PUMA and Noxa. Importantly, p53R172P MEFs failed to downregulate anti-apoptotic protein Bcl-2, which has been shown to play an important role in p53-dependent apoptosis. Taken together, these data demonstrate that in the absence of p53-mediated apoptosis, cells undergo cellular senescence to prevent genomic instability. Our results also indicate that p53-dependent apoptosis may play an active role in balancing cellular growth.
AB - Genotoxic stress triggers the p53 tumor suppressor network to activate cellular responses that lead to cell cycle arrest, DNA repair, apoptosis or senescence. This network functions mainly through transactivation of different downstream targets, including cell cycle inhibitor p21, which is required for short-term cell cycle arrest or long-term cellular senescence, or proapoptotic genes such as p53 upregulated modulator of apoptosis (PUMA) and Noxa. However, the mechanism that switches from cell cycle arrest to apoptosis is still unknown. In this study, we found that mice harboring a hypomorphic mutant p53, R172P, a mutation that abrogates p53-mediated apoptosis while keeping cell cycle control mostly intact, are more susceptible to ultraviolet-B (UVB)-induced skin damage, inflammation and immunosuppression than wild-type mice. p53 R172P embryonic fibroblasts (MEFs) are hypersensitive to UVB and prematurely senesce after UVB exposure, in stark contrast to wild-type MEFs, which undergo apoptosis. However, these mutant cells are able to repair UV-induced DNA lesions, indicating that the UV hypersensitive phenotype results from the subsequent damage response. Mutant MEFs show an induction of p53 and p21 after UVR, while wild-type MEFs additionally induce PUMA and Noxa. Importantly, p53R172P MEFs failed to downregulate anti-apoptotic protein Bcl-2, which has been shown to play an important role in p53-dependent apoptosis. Taken together, these data demonstrate that in the absence of p53-mediated apoptosis, cells undergo cellular senescence to prevent genomic instability. Our results also indicate that p53-dependent apoptosis may play an active role in balancing cellular growth.
KW - Apoptosis
KW - DNA damage
KW - DNA damage responses
KW - Senescence
KW - UVB irradiation
KW - p53
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U2 - 10.4161/cc.9.16.12688
DO - 10.4161/cc.9.16.12688
M3 - Article
C2 - 20703098
AN - SCOPUS:77955763927
SN - 1538-4101
VL - 9
SP - 3348
EP - 3356
JO - Cell Cycle
JF - Cell Cycle
IS - 16
ER -