Regulation of MDMX expression by mitogenic signaling

Daniele M. Gilkes, Yu Pan, Domenico Coppola, Timothy Yeatman, Gary W. Reuther, Jiandong Chen

Research output: Contribution to journalArticlepeer-review

Abstract

MDMX is an important regulator of p53 transcriptional activity and stress response. MDMX overexpression and gene amplification are implicated in p53 inactivation and tumor development. Unlike MDM2, MDMX is not inducible by p53, and little is known about its regulation at the transcriptional level. We found that MDMX levels in tumor cell lines closely correlate with promoter activity and mRNA level. Activated K-Ras and insulin-like growth factor 1 induce MDMX expression at the transcriptional level through mechanisms that involve the mitogen-activated protein kinase and c-Ets-1 transcription factors. Pharmacological inhibition of MEK results in down-regulation of MDMX in tumor cell lines. MDMX overexpression was detected in ∼50% of human colon tumors and showed strong correlation with increased extracellular signal-regulated kinase phosphorylation. Therefore, MDMX expression is regulated by mitogenic signaling pathways. This mechanism may protect normal proliferating cells from p53 but also hamper p53 response during tumor development.

Original languageEnglish (US)
Pages (from-to)1999-2010
Number of pages12
JournalMolecular and cellular biology
Volume28
Issue number6
DOIs
StatePublished - Mar 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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