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Resistance to UV‐induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53
Author(s) -
Chaturvedi V.,
Qin J.Z.,
Stennett L.,
Choubey D.,
Nickoloff B.J.
Publication year - 2004
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10392
Subject(s) - senescence , apoptosis , microbiology and biotechnology , resistance (ecology) , keratinocyte , biology , chemistry , cell culture , genetics , ecology
Compared to proliferating keratinocytes (KCs), growth‐arrested KCs are relatively resistant to UV‐light induced apoptosis. When KCs undergo confluency, or following exposure to anti‐proliferative agents such as IFN‐γ plus a phorbol ester–12‐ O ‐tetradecanoylyphorbol‐13‐acetate (TPA), they convert from a proliferative to a nonproliferative state resembling senescence. Since p53 regulates UV‐induced apoptosis of KCs, this report further characterizes p53 half‐life, post‐translational modifications, and transcriptional activity using cultured human KCs and living epidermal equivalents. The half‐life of p53 in KCs was longer than fibroblasts (greater than approximately 3 h vs. 30 min). Exposure of proliferating KCs to UV‐light induces post‐translational modifications of p53 including acetylation of lysine‐382 residues. By contrast, KCs undergoing irreversible growth arrest following confluency, or exposure to IFN‐γ plus TPA, were resistant to UV‐induced apoptosis, and failed to undergo the acetylation modification of p53. Exposure of KCs to IFN‐γ plus TPA reduced total cellular p53 levels and reduced the transcriptional activity of p53. Addition of Trichostatin A (TSA), an inhibitor of de‐acetylation, increased acetylation of lysine‐382 in confluent KCs, thereby enhancing susceptibility of confluent cultures to UV‐induced apoptosis. Pre‐treatment of epidermal equivalents with IFN‐γ plus TPA also blocked UV‐light induced increase in p53 levels, and reduced apoptosis. In conclusion, these studies demonstrate that growth arrested KCs may resist UV‐light induced apoptosis by inactivating the pro‐apoptotic function of p53. J. Cell. Physiol. 198: 100–109, 2004. © 2003 Wiley‐Liss, Inc.