Mitogen-activated Protein Kinase Phosphorylates and Targets Inducible cAMP Early Repressor to Ubiquitin-mediated Destruction

Ghassan Yehia, Florence Schlotter, Reza Razavi, Alessandro Alessandrini, Carlos Molina

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Inducible cAMP early repressor (ICER) is an important mediator of cAMP antiproliferative activity that acts as a putative tumor suppressor gene product. In this study, we examined the regulation of ICER protein by phosphorylation and ubiquitination in human choriocarcinoma JEG-3 and mouse pituitary AtT20 cells. We found that cAMP stabilized ICER protein by inhibiting the mitogen-activated protein kinase (MAPK) cascade. Activation of the MAPK pathway increased ICER phosphorylation. ICER phosphorylation was abrogated by inhibition of the MAPK pathway either by cAMP or directly by the MAPK inhibitor PD098059. The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway. These results present a novel cell signaling cross-talk mechanism at the cell nucleus between the MAPK and cAMP pathways, whereby MAPK targets a repressor of the cAMP-dependent gene expression for ubiquitination and proteasomal degradation.

Original languageEnglish
Pages (from-to)35272-35279
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number38
DOIs
StatePublished - 21 Sep 2001

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Ubiquitin
Mitogen-Activated Protein Kinases
Phosphorylation
Repressor Proteins
Ubiquitination
MAP Kinase Kinase 2
Cell signaling
Choriocarcinoma
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Proteasome Endopeptidase Complex
Protein Kinase Inhibitors
Tumor Suppressor Genes
Cell Nucleus
Gene expression
Alanine
Serine
Half-Life
Tumors
Genes

Cite this

Yehia, Ghassan ; Schlotter, Florence ; Razavi, Reza ; Alessandrini, Alessandro ; Molina, Carlos. / Mitogen-activated Protein Kinase Phosphorylates and Targets Inducible cAMP Early Repressor to Ubiquitin-mediated Destruction. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 38. pp. 35272-35279.
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Mitogen-activated Protein Kinase Phosphorylates and Targets Inducible cAMP Early Repressor to Ubiquitin-mediated Destruction. / Yehia, Ghassan; Schlotter, Florence; Razavi, Reza; Alessandrini, Alessandro; Molina, Carlos.

In: Journal of Biological Chemistry, Vol. 276, No. 38, 21.09.2001, p. 35272-35279.

Research output: Contribution to journalArticle

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