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Carcinogenesis Advance Access published online on April 2, 2007
Carcinogenesis, 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 Zykova, Feng Zhu, Yiguo Zhang, Ann M. Bode and Zigang Dong*

Hormel Institute, University of Minnesota,{dagger}, 801 16th Avenue NE, Austin, Minnesota 55912, USA

* To whom correspondence should be addressed at: Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Tel: 507-437-9600; Fax: 507-437-9606; E-mail: zgdong{at}hi.umn.edu.

Double-stranded RNA-dependent protein kinase R (PKR) has been implicated in anti-viral, anti-tumor, 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 of ERK2 or RSK2 deficient cells (RSK2-). An inhibitor of p38, SB 202190, or a dominant negative mutant 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.

Key Words: UVA • PKR • eIF2{alpha} • ERK2 • RSK2 • phosphorylation

{dagger} The University of Minnesota is an equal opportunity educator and employer.

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


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