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Molecular and Cellular Biology, October 2008, p. 5951-5964, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00305-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Gene Signature-Based Approach Identifies mTOR as a Regulator of p73{triangledown}

Jennifer M. Rosenbluth, Deborah J. Mays,{dagger} Maria F. Pino,{dagger} Luo Jia Tang, and Jennifer A. Pietenpol*

Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Received 22 February 2008/ Returned for modification 17 May 2008/ Accepted 27 July 2008

Although genomic technologies have advanced the characterization of gene regulatory networks downstream of transcription factors, the identification of pathways upstream of these transcription factors has been more challenging. In this study we present a gene signature-based approach for connecting signaling pathways to transcription factors, as exemplified by p73. We generated a p73 gene signature by integrating whole-genome chromatin immunoprecipitation and expression profiling. The p73 signature was linked to corresponding signatures produced by drug candidates, using the in silico Connectivity Map resource, to identify drugs that would induce p73 activity. Of the pharmaceutical agents identified, there was enrichment for direct or indirect inhibitors of mammalian Target of Rapamycin (mTOR) signaling. Treatment of both primary cells and cancer cell lines with rapamycin, metformin, and pyrvinium resulted in an increase in p73 levels, as did RNA interference-mediated knockdown of mTOR. Further, a subset of genes associated with insulin response or autophagy exhibited mTOR-mediated, p73-dependent expression. Thus, downstream gene signatures can be used to identify upstream regulators of transcription factor activity, and in doing so, we identified a new link between mTOR, p73, and p73-regulated genes associated with autophagy and metabolic pathways.

* Corresponding author. Mailing address: Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 936-1512. Fax: (615) 936-2294. E-mail: j.pietenpol{at}vanderbilt.edu

{triangledown} Published ahead of print on 4 August 2008.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, October 2008, p. 5951-5964, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00305-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Schrump, D. S. (2009). Cytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical Implications. Clin. Cancer Res. 15: 3947-3957 [Abstract] [Full Text]  


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