Disassociation of MAPK Activation and c-Fos Expression in F9 Embryonic Carcinoma Cells following Retinoic Acid-induced Endoderm Differentiation

Elizabeth R. Smith, Jennifer L. Smedberg, Malgorzata E. Rula, Thomas C. Hamilton, Xiangxi Xu

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Retinoic acid induces cell differentiation and suppresses cell growth in a wide spectrum of cell lines, and down-regulation of activator protein-1 activity by retinoic acid contributes to these effects. In embryonic stem cell-like F9 teratocarcinoma cells, which are widely used to study retinoic acid actions on gene regulation and early embryonic differentiation, retinoic acid treatment for 4 days resulted in suppression of cell growth and differentiation into primitive and then visceral endoderm-like cells, accompanied by a suppression of serum-induced c-Fos expression. The MAPK (ERK) pathway was involved in mitogenic signaling in F9 cells stimulated with serum. Surprisingly, although c-Fos expression was reduced, the MAPK activity was not decreased by retinoic acid treatment. We found that retinoic acid treatment inhibited the phosphorylation of Elk-1, a target of activated MAPK required for c-Fos transcription. In F9 cells, the MAPK/MEK inhibitor PD98059 suppressed Elk-1 phosphorylation and c-Fos expression, indicating that MAPK activity is required for Elk-1 phosphorylation/activation. Phosphoprotein phosphatase 2B (calcineurin), the major phosphatase for activated Elk-1, is not the target in the disassociation of MAPK activation and c-Fos expression since its inhibition by cyclosporin A or activation by ionomycin had no significant effects on serum-stimulated c-Fos expression and Elk-1 phosphorylation. Thus, we conclude that retinoic acid treatment to induce F9 cell differentiation uncouples Ras/MAPK activation from c-Fos expression by reduction of Elk-1 phosphorylation through a mechanism not involving the activation of phosphoprotein phosphatase 2B.

Original languageEnglish
Pages (from-to)32094-32100
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number34
DOIs
StatePublished - Aug 24 2001
Externally publishedYes

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Endoderm
Tretinoin
Phosphorylation
Chemical activation
Cells
Carcinoma
Cell Differentiation
Phosphoprotein Phosphatases
Cell growth
Serum
Teratocarcinoma
Ionomycin
MAP Kinase Signaling System
Calcineurin
Mitogen-Activated Protein Kinase Kinases
Transcription Factor AP-1
Gene Expression Regulation
Transcription
Embryonic Stem Cells
Growth

ASJC Scopus subject areas

  • Biochemistry

Cite this

Disassociation of MAPK Activation and c-Fos Expression in F9 Embryonic Carcinoma Cells following Retinoic Acid-induced Endoderm Differentiation. / Smith, Elizabeth R.; Smedberg, Jennifer L.; Rula, Malgorzata E.; Hamilton, Thomas C.; Xu, Xiangxi.

In: Journal of Biological Chemistry, Vol. 276, No. 34, 24.08.2001, p. 32094-32100.

Research output: Contribution to journalArticle

Smith, Elizabeth R. ; Smedberg, Jennifer L. ; Rula, Malgorzata E. ; Hamilton, Thomas C. ; Xu, Xiangxi. / Disassociation of MAPK Activation and c-Fos Expression in F9 Embryonic Carcinoma Cells following Retinoic Acid-induced Endoderm Differentiation. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 34. pp. 32094-32100.
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