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PMID: 18678646 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Validation Study

A gene signature-based approach identifies mTOR as a regulator of p73.

Molecular and cellular biology ·Vol. 28 ·No. 19 ·2008-10-00 ·Pages 5951-64

Rosenbluth JM, Mays DJ, Pino MF, Tang LJ, Pietenpol JA

Abstract

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.

MeSH Terms
Cell Line Cell Line, Tumor Chromatin Immunoprecipitation DNA-Binding Proteins/genetics,metabolism Genomics/methods Humans Nuclear Proteins/genetics,metabolism Protein Kinases/metabolism Signal Transduction TOR Serine-Threonine Kinases Tumor Protein p73 Tumor Suppressor Proteins/genetics,metabolism
Chemicals
DNA-Binding Proteins Nuclear Proteins TP73 protein, human Tumor Protein p73 Tumor Suppressor Proteins Protein Kinases MTOR protein, human TOR Serine-Threonine Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Rosenbluth Jennifer M
Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Mays Deborah J
Pino Maria F
Tang Luo Jia
Pietenpol Jennifer A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.00305-08
Published
2008-10-00
Epub
2008-00-04
Pages
5951-64
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2547001
Subset
IM
Grants
NIGMS NIH HHS · GM07347 · United States
NCI NIH HHS · R01 CA105436 · United States
NCI NIH HHS · R01 CA070856 · United States
NIGMS NIH HHS · T32 GM007347 · United States
NCI NIH HHS · P30 CA068485 · United States
NIEHS NIH HHS · ES00267 · United States
NIEHS NIH HHS · P30 ES000267 · United States
NCI NIH HHS · CA105436 · United States
NCI NIH HHS · CA68485 · United States
NCI NIH HHS · CA70856 · United States
External Links
PubMed source DOI: 10.1128/MCB.00305-08 PMC Full Text View journal details
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