Journal Article

Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1

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

in Carcinogenesis

Volume 25, issue 7, pages 1165-1175
Published in print July 2004 | ISSN: 0143-3334
Published online July 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh115
Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1

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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 c-Jun N-terminal kinases (JNKs), respectively. STAT1 phosphorylation was also blocked by a dominant negative mutant of p38β kinase or JNK1, JNK1- or JNK2-deficiency, or an N-terminal or C-terminal kinase-dead mutant of mitogen- and stress-activated 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 pull down 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.

Keywords: CMVS, pCMV5-FLAG vector; DMEM, Dulbecco's modified Eagle's medium; DNM-JNK1, dominant negative mutant of JNK1; DNM-p38β, dominant negative mutant of p38β kinase; EGF, epidermal growth factor; ERKs, extracellular signal-regulated kinases; FBS, fetal bovine serum; GST, glutathione S-transferase; JAK, Janus kinase; JNKs, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinases; MSK1, mitogen- and stress-activated protein kinase 1; STAT1, signal transducer and activator of transcription 1

Journal Article.  7385 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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