Negative Regulation of ERK and Elk by Protein Kinase B Modulates c-fos Transcription

Ivana Galetic,Sauveur-Michel Maira,Mirjana Andjelkovic,Brian A Hemmings

doi:10.1074/jbc.m210578200

Ivana Galetic, Sauveur-Michel Maira + Show 2 more

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https://doi.org/10.1074/jbc.m210578200

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Abstract

In this study, we have identified novel regulatory steps involved in the cross-talk between protein kinase B (PKB) and MAPK signaling pathways. We found that PKB down-regulates the Ras-Raf-MEK-ERK pathway by reducing the activity of ERK, which leads to inactivation of the transcription factor Elk1. In addition, PKB is able to reduce protein levels of Elk1. Both events lead to suppression of serum response element (SRE)-dependent transcription and a consequent decrease in the transcription of SRE-containing genes, such as c-fos. Because activation of the Ras/MAPK cascade is reported to increase c-fos transcription before apoptosis, our results are consistent with a specific role for PKB in promoting cell survival. Decrease in c-Fos protein levels in glioblastoma cells with constitutively active PKB provides further support for our observations. Therefore, our findings delineate a novel mechanism regulating immediate-early transcription, which may be involved in the initial steps in PKB-induced oncogenic transformation.

Highlights

Protein kinase B (PKB,1 termed Akt) belongs to a family of serine/threonine kinases that are down-stream of the phosphoinositide 3-kinase (PI3K)
Protein Kinase B Is Able to Suppress Transcription from the serum response element (SRE)—To investigate possible cross-talk between protein kinase B (PKB) and other signaling cascades, we performed a screen of signal transduction pathways by monitoring the transcriptional activity of several reporter constructs
We used the Secreted alkaline phosphatase (SEAP) reporter system, where a specific response element is located upstream of a minimal thymidine kinase promoter fused to secreted alkaline phosphatase

Summary

Introduction

Protein kinase B (PKB, termed Akt) belongs to a family of serine/threonine kinases that are down-stream of the phosphoinositide 3-kinase (PI3K). It was reported recently that PKB phosphorylates Mdm and, promotes its nuclear translocation This leads to increased ubiquitination of p53 and resistance to apoptosis in some cancer cells [9, 10]. Another key mediator of cellular response to external stimuli is the mitogen-activated protein kinase pathway, which is highly conserved in all eukaryotes ERK translocates to the nucleus and regulates the activity of many transcription factors, which results in distinct biological responses ERK translocates to the nucleus and regulates the activity of many transcription factors, which results in distinct biological responses (for review, see Refs. 11 and 12)

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