Protein kinase C mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2)

M. H. Aziz, Bilal Hafeez, J. M. Sand, D. B. Pierce, S. W. Aziz, N. E. Dreckschmidt, A. K. Verma

Research output: Contribution to journalArticle

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Abstract

Protein kinase C epsilon (PKC), a novel calcium-independent PKC isoform, has been shown to be a transforming oncogene. PKC-mediated oncogenic activity is linked to its ability to promote cell survival. However, the mechanisms by which PKC signals cell survival remain elusive. We found that signal transducers and activators of transcription 3 (Stat3), which is constitutively activated in a wide variety of human cancers, is a protein partner of PKC. Stat3 has two conserved amino-acid (Tyr705 and Ser727) residues, which are phosphorylated during Stat3 activation. PKC interacts with Stat3α isoform, which has Ser727, and not with Stat3Β isoform, which lacks Ser727. PKC-Stat3 interaction and Stat3Ser727 phosphorylation was initially observed during induction of squamous cell carcinomas and in prostate cancer. Now we present that (1) PKC physically interacts with Stat3α isoform in various human cancer cells: skin melanomas (MeWo and WM266-4), gliomas (T98G and MO59K), bladder (RT-4 and UM-UC-3), colon (Caco-2), lung (H1650), pancreatic (PANC-1), and breast (MCF-7 and MDA:MB-231); (2) inhibition of PKC expression using specific siRNA inhibits Stat3Ser727 phosphorylation, Stat3-DNA binding, Stat3-regulated gene expression as well as cell invasion; and (3) PKC mediates Stat3Ser727 phosphorylation through integration with the MAPK cascade (RAF-1, MEK1/2, and ERK1/2). The results indicate that PKC-mediated Stat3Ser727 phosphorylation is essential for constitutive activation of Stat3 and cell invasion in various human cancers.

Original languageEnglish (US)
Pages (from-to)3100-3109
Number of pages10
JournalOncogene
Volume29
Issue number21
DOIs
StatePublished - May 27 2010

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Protein Kinase C-epsilon
STAT3 Transcription Factor
Protein Kinase C
Phosphorylation
Gene Expression
Cell Line
Neoplasms
Protein Isoforms
Cell Survival
Skin Neoplasms
Oncogenes
Glioma
Small Interfering RNA
Transcriptional Activation
Squamous Cell Carcinoma
Melanoma
Prostatic Neoplasms
Colon
Urinary Bladder
Breast

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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Protein kinase C mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2). / Aziz, M. H.; Hafeez, Bilal; Sand, J. M.; Pierce, D. B.; Aziz, S. W.; Dreckschmidt, N. E.; Verma, A. K.

In: Oncogene, Vol. 29, No. 21, 27.05.2010, p. 3100-3109.

Research output: Contribution to journalArticle

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AU - Sand, J. M.

AU - Pierce, D. B.

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AU - Dreckschmidt, N. E.

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