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Roles of protein kinase C and alpha-tocopherol in regulation of signal transduction for GATA-4 phosphorylation in HL-1 cardiac muscle cells.

Abstract
Our previous study demonstrated that endothelin-1 induced a phosphorylation of GATA-4 transcription factor, which plays important roles in cardiac hypertrophy and failure. The goal of the present study was to determine whether protein kinase C (PKC) is involved in the signaling pathway, and, if so, whether alpha-tocopherol inhibits the GATA-4 phosphorylation. Treatment of HL-1 adult mouse cardiac muscle cells with PMA, a known activator of PKC, induced a transient phosphorylation of GATA-4. PMA also phosphorylated MEK and ERK, and PMA-induced GATA-4 phosphorylation was blocked by an MEK inhibitor, PD98059, suggesting that PMA phosphorylates GATA-4 via the MEK-ERK pathway. Treatment of HL-1 cells with 1 microM PMA for 24 h resulted in a downregulation of PKC. In PKC-downregulated cells, PMA- or ET-1-induced GATA-4 phosphorylation was suppressed, suggesting the role of PKC in GATA-4 phosphorylation. However, alpha-tocopherol (5--100 microM) did not inhibit the phosphorylation of GATA-4 or ERK in HL-1 cells. In contrast, alpha-tocopherol potently inhibited the PMA-induced ERK activation in smooth muscle cells. Our studies in HL-1 cells showed that PKC inhibitors, such as calphostin C and chelerythrin, failed to inhibit the PMA signaling. Furthermore, HL-1 cells appear to possess a unique PKC-signaling mechanism as PKC is constitutively phosphorylated and PMA did not cause further phosphorylation. Thus, in HL-1 cardiac muscle cells, PMA activates the MEK-ERK-GATA-4 pathway, apparently via a PKC-independent mechanism.
AuthorsSophie A Clément, Chia Chi Tan, Jianli Guo, Kazumi Kitta, Yuichiro J Suzuki
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 32 Issue 4 Pg. 341-9 (Feb 15 2002) ISSN: 0891-5849 [Print] United States
PMID11841924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Alkaloids
  • Benzophenanthridines
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Free Radicals
  • GATA4 Transcription Factor
  • Naphthalenes
  • Phenanthridines
  • Transcription Factors
  • chelerythrine
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • alpha-Tocopherol
  • calphostin C
Topics
  • Alkaloids
  • Animals
  • Benzophenanthridines
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins (metabolism)
  • Down-Regulation
  • Enzyme Inhibitors (pharmacology)
  • Free Radicals
  • GATA4 Transcription Factor
  • Mice
  • Mitogen-Activated Protein Kinases (metabolism)
  • Myocardium (cytology)
  • Naphthalenes (metabolism)
  • Phenanthridines (metabolism)
  • Phosphorylation
  • Protein Kinase C (metabolism, physiology)
  • Signal Transduction
  • Time Factors
  • Transcription Factors (metabolism)
  • alpha-Tocopherol (metabolism)

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