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Carcinogenesis Advance Access published online on February 12, 2004
Carcinogenesis, doi:10.1093/carcin/bgh115
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CANCER BIOLOGY

Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1

Yiguo Zhang 1, Yong-Yeon Cho 1, Brandon L. Petersen 1, Feng Zhu 1, and Zigang Dong 1*

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

* Corresponding author. E-mail: zgdong{at}hi.umn.edu.

Received 25 November 2003 ; revised 26 January 2004 ; accepted 4 February 2004

Abstract

Phosphorylation at Ser727 in signal transducer and activator of transcription 1 (STAT1) is essential for its activation and signal transduction. However, the upstream kinases responsible for phosphorylating Ser727 are still elusive. Here, we provide evidence showing that UVA-induced mitogen-activated protein kinase (MAPK) signaling pathways lead to STAT1 Ser727 phosphorylation. Our experimental results show that UVA-induced Ser727 phosphorylation of STAT1 was, to different degrees, diminished by PD98059 and U0126, two specific inhibitors of MEKs, and SB202190 and PD169316, inhibitors of p38 kinase and/or c-Jun N-terminal kinases (JNKs), respectively. STAT1 phosphorylation was also blocked by a dominant negative mutant of p38{beta} kinase or JNK1, JNK1- or JNK2- deficiency, or an N- terminal or C- terminal kinase-dead mutant of mitogen- and stressactivated protein kinase 1 (MSK1), a downstream kinase closer to p38 kinase and extracellular signal-regulated kinases (ERKs). In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S-transferase (GST) pulldown show that active ERK1, JNK1, p38 kinase, MEK1 and MSK1 stimulated phosphorylation of STAT1 (Ser727) indirectly through an unidentified factor or a downstream kinase. Overall, our data indicate that phosphorylation of STAT1 at Ser727 occurs through diverse MAPK cascades including MEK1, ERKs, p38 kinase, JNKs and MSK1 in the cellular response to UVA.


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