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Molecular and Cellular Biology, March 2008, p. 1999-2010, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01633-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of MDMX Expression by Mitogenic Signaling{triangledown}

Daniele M. Gilkes,1 Yu Pan,1,{dagger} Domenico Coppola,2 Timothy Yeatman,3 Gary W. Reuther,1 and Jiandong Chen1*

Molecular Oncology Program,1 Division of Anatomic Pathology,2 Department of Surgery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 336123

Received 4 September 2007/ Returned for modification 3 October 2007/ Accepted 22 December 2007

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.

* Corresponding author. Mailing address: H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Drive, Tampa, FL 33612. Phone: (813) 903-6822. Fax: (813) 903-6817. E-mail: Jiandong.chen{at}moffitt.org

{triangledown} Published ahead of print on 2 January 2008.

{dagger} Present address: Shands Cancer Center, University of Florida, Gainesville, FL.

Molecular and Cellular Biology, March 2008, p. 1999-2010, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01633-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wade, M., Wahl, G. M. (2009). Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry?. Mol Cancer Res 7: 1-11 [Abstract] [Full Text]  


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