Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence

Omid Tavana, Cara Benjamin, Nahum Puebla-Osorio, Mei Sang, Stephen E. Ullrich, Honnavara N. Ananthaswamy, Chengming Zhu

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3328-3336
Number of pages9
JournalCell Cycle
Volume9
Issue number16
DOIs
StatePublished - Aug 15 2010

Fingerprint

Cell Aging
Immunosuppression
Hypersensitivity
Radiation
Apoptosis
Cell Cycle Checkpoints
Noxae
Apoptosis Regulatory Proteins
Genomic Instability
DNA Repair
Transcriptional Activation
DNA Damage
Cell Cycle
Down-Regulation
Fibroblasts
Inflammation
Phenotype
Skin
Mutation
DNA

Keywords

  • Apoptosis
  • DNA damage
  • DNA damage responses
  • p53
  • Senescence
  • UVB irradiation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence. / Tavana, Omid; Benjamin, Cara; Puebla-Osorio, Nahum; Sang, Mei; Ullrich, Stephen E.; Ananthaswamy, Honnavara N.; Zhu, Chengming.

In: Cell Cycle, Vol. 9, No. 16, 15.08.2010, p. 3328-3336.

Research output: Contribution to journalArticle

Tavana, Omid ; Benjamin, Cara ; Puebla-Osorio, Nahum ; Sang, Mei ; Ullrich, Stephen E. ; Ananthaswamy, Honnavara N. ; Zhu, Chengming. / Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence. In: Cell Cycle. 2010 ; Vol. 9, No. 16. pp. 3328-3336.
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