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Vol. 19, Issue 4, 1346-1353, April 2008

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UVB-induced Senescence in Human Keratinocytes Requires a Functional Insulin-like Growth Factor-1 Receptor and p53

Davina A. Lewis^*, Qiaofang Yi^*,, Jeffrey B. Travers^*,,,, and Dan F Spandau^*,||

Departments of *Dermatology and Pharmacology and Toxicology, Herman B. Wells Center for Pediatric Research, Richard L. Roudebush V.A. Medical Center, and ^||Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5121

Submitted October 16, 2007; Revised January 7, 2008; Accepted January 16, 2008
Monitoring Editor: J. Silvio Gutkind

To cope with the frequent exposure to carcinogenic UV B (UVB) wavelengths found in sunlight, keratinocytes have acquired extensive protective measures to handle UVB-induced DNA damage. Recent in vitro and epidemiological data suggest one these protective mechanisms is dependent on the functional status of the insulin-like growth factor-1 receptor (IGF-1R) signaling network in keratinocytes. During the normal UVB response, ligand-activated IGF-1Rs protect keratinocytes from UVB-induced apoptosis; however, as a consequence, these keratinocytes fail to proliferate. This adaptive response of keratinocytes to UVB exposure maintains the protective barrier function of the epidermis while ensuring that UVB-damaged keratinocytes do not replicate DNA mutations. In contrast, when keratinocytes are exposed to UVB in the absence of IGF-1R activation, the keratinocytes are more sensitive to UVB-induced apoptosis, but the surviving keratinocytes retain the capacity to proliferate. This aberrant UVB response represents flawed protection from UVB damage potentially resulting in the malignant transformation of keratinocytes. Using normal human keratinocytes grown in vitro, we have demonstrated that activation of the IGF-1R promotes the premature senescence of UVB-irradiated keratinocytes through increased generation of reactive oxygen species (ROS) and by maintaining the expression of the cyclin-dependent kinase inhibitor p21^CDKN1A. Furthermore, IGF-1R–dependent UVB-induced premature senescence required the phosphorylation of p53 serine 46. These data suggest one mechanism of keratinocyte resistance to UVB-induced carcinogenesis involves the induction of IGF-1R–dependent premature senescence.

Address correspondence to: Dan F Spandau (dspanda{at}iupui.edu.

Abbreviations used: IGF-1R, insulin-like growth factor-1 receptor; PBS, phosphate-buffered saline; UVB, ultraviolet B.

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