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Carcinogenesis Advance Access published online on June 10, 2004
Carcinogenesis, doi:10.1093/carcin/bgh202
© 2004 by Oxford University Press
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Received February 5, 2004
Revised April 30, 2004
Accepted May 27, 2004

CANCER BIOLOGY

Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells

Feng Zhu 1, Yiguo Zhang 1, Ann M. Bode 1, Zigang Dong 1*

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

* To whom correspondence should be addressed. E-mail: zgdong{at}hi.umn.edu.


  Abstract

Activating transcription factor 2 (ATF2) has been shown to regulate gene expression in the cellular response to environmental stresses such as ultraviolet (UV) irradiation. However, the signal transduction mechanism of ATF2 activation by UV is not as yet completely understood. In the present study, we provide evidence showing that UVC-stimulated phosphorylation of ATF2 (Thr71) was to varying degrees prevented by a dominant negative mutant of p38{beta} kinase, c-Jun N-terminal kinase 1 (JNK1), or extracellular signal-regulated kinase 2 (ERK2). The phosphorylation was also suppressed by PD98059, a MEK inhibitor, or H89, a potent inhibitor of mitogen- and stress-activated protein kinase 1 (MSK1), and a C- or N-terminal "kinase-dead" mutant of MSK1 (MSK1-Cd or MSK1-Nd). Furthermore, co-immunoprecipitation experiments revealed a potential intracellular signaling complex consisting of ATF2 and ERKs and/or MSK1. In vitro kinase assays revealed that ERK1, ERK2, and MSK1, like p38 kinase and JNK2, directly phosphorylate ATF2 at Thr71, but addition of RSK2 or Akt1 had almost no effect. Active kinase immunoprecipitated by a MSK1, ERKs, or p38 antibody from an extract of JB6 cells irradiated by UVC can directly phosphorylate ATF2 at Thr71, suggesting UVC induces a direct phosphorylation of ATF2 by ERKs or MSK1. Overall, our results reveal that MSK1 and ERKs, like p38 kinase and JNKs, are required for ATF2 phosphorylation (Thr71) in the UVC response.

Key Words: ERKs, JNKs, p38 kinase, MSK1, UV, ATF2,


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