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Carcinogenesis Advance Access originally published online on April 2, 2007
Carcinogenesis 2007 28(7):1543-1551; doi:10.1093/carcin/bgm070
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Involvement of ERKs, RSK2 and PKR in UVA-induced signal transduction toward phosphorylation of eIF2{alpha} (Ser51)

Tatyana A. Zykova, Feng Zhu, Yiguo Zhang, Ann M. Bode and Zigang Dong*

Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA

* To whom correspondence should be addressed. Tel: +507 437 9600; Fax: +507 437 9606; Email: zgdong{at}hi.umn.edu

Double-stranded RNA-dependent protein kinase R (PKR) has been implicated in anti-viral (antitumor) and apoptotic responses. PKR is activated by extracellular stresses and phosphorylates the {alpha} subunit of protein synthesis initiation factor eIF2, thereby inhibiting protein synthesis and impeding virus multiplication. Phosphorylation of eIF2{alpha} in mammalian cells has been shown to be increased after ultraviolet (UV) stress and to be required for UV-induced repression of protein translation. UVA is an important etiological factor in skin carcinogenesis and we observed that UVA induced phosphorylation of PKR (Thr451) and eIF2{alpha} (Ser51) in mouse skin epidermal JB6 Cl41 cells. The induction was suppressed by the MEK1 inhibitor, PD 98059. UVA stimulation of PKR and eIF2{alpha} phosphorylation was also inhibited by a dominant-negative mutant (DNM) of ERK2- or RSK2-deficient cells (RSK2–). An inhibitor of p38, SB 202190 or a DNM of p38{alpha} kinase (DNM-p38{alpha}) suppressed UVA-induced phosphorylation of eIF2{alpha} (Ser51) but had no effect on phosphorylation of PKR (Thr451). Our data indicated that phosphorylation of PKR at Thr451 is mediated through ERK2 and RSK2, but not through p38 kinase, and is involved in the regulation of Ser51 phosphorylation of eIF2{alpha} in UVA-irradiated JB6 cells. In vitro and in vivo kinase assays indicated that phosphorylation of eIF2{alpha} at Ser51 occurred indirectly through ERK2, RSK2 or p38 kinase in the cellular response to UVA. These data may lead to the use of these signaling molecules as targets to develop more effective chemopreventive agents with fewer side effects to control UV-induced skin cancer.

Abbreviations: DNM, dominant-negative mutant; dsRNA, double-stranded RNA; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; IP, immunoprecipitation; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEM, minimum essential medium; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; PKR, protein kinase R; SDS, sodium dodecyl sulfate; UV, ultraviolet

Received January 12, 2007; revised March 9, 2007; accepted March 19, 2007.


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