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J. Biol. Chem., Vol. 279, Issue 41, 42658-42668, October 8, 2004

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Ultraviolet A-induced Modulation of Bcl-X_L by p38 MAPK in Human Keratinocytes

POST-TRANSCRIPTIONAL REGULATION THROUGH THE 3'-UNTRANSLATED REGION^*

Michael A. Bachelor and G. Timothy Bowden

From the Department of Cell Biology and Anatomy, Arizona Cancer Center, the University of Arizona, Tucson, Arizona 85724

We examined the effect of inhibiting p38 MAPK on UVA-irradiated HaCaT cells, a spontaneously immortalized human keratinocyte cell line. Recent work from our laboratory has shown that UVA (250 kJ/m²) induces a rapid phosphorylation of p38 MAPK in the HaCaT cell line. Inhibition of p38 MAPK activity through the use of a specific inhibitor, SB202190, in combination with UVA treatment induced a rapid cleavage of caspase-9, caspase-8, and caspase-3, whereas UVA irradiation alone had no effect. Similarly, cleavage of the caspase substrate poly(ADP-ribose) polymerase was observed in UVA-irradiated HaCaT cells treated with SB202190 or in cells expressing a dominant-negative p38 MAPK. No effect of p38 MAPK inhibition upon caspase cleavage was observed in mock-irradiated HaCaT cells. In addition, increases in apoptosis were observed in UVA-irradiated cells treated with SB202190 by morphological analysis with no significant apoptosis occurring from UVA irradiation alone. Similar results were obtained by using normal human epidermal keratinocytes. UVA induced expression of the anti-apoptotic Bcl-2 family member, Bcl-X_L, with abrogation of expression by using the p38 MAPK inhibitor SB202190. Overexpression of Bcl-X_L prevented poly(ADP-ribose) polymerase cleavage induced by the combination of UVA and p38 MAPK inhibition. UVA enhanced the stability of Bcl-X_L mRNA through increases in p38 MAPK activity. We determined that increases in UVA-induced expression of Bcl-X_L occur through a posttranscriptional mechanism mediated by the 3'-untranslated region (UTR). We used Bcl-X_L 3'-UTR luciferase constructs to determine the mechanism by which UVA increased Bcl-X_L mRNA stability. Additionally, RNA binding studies indicate that UVA increases the binding of RNA-binding proteins to Bcl-X_L 3'-UTR mRNA, which can be decreased by using SB202190. In conclusion, p38 MAPK and Bcl-X_L expression play critical roles in the survival of UVA-irradiated HaCaT cells.

Received for publication, June 14, 2004 , and in revised form, July 23, 2004.

^* This work was supported by National Institutes of Health Grants CA27502 and CA23074 and the Achievement Rewards for College Scientists Foundation (to M. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Arizona Cancer Center, the University of Arizona, 1515 N. Campbell Ave., Rm. 4999, Tucson, AZ 85724. Tel.: 520-626-6006; Fax: 520-626-4979; E-mail: tbowden{at}azcc.arizona.edu.

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