Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis.

Rosenbluth JM, Mays DJ, Jiang A, Shyr Y, Pietenpol JA
Proc Natl Acad Sci U S A. 2011 108 (5): 2076-81

PMID: 21245298 · PMCID: PMC3033306 · DOI:10.1073/pnas.1011936108

The transcription factor p73 plays critical roles during development and tumorigenesis. It exhibits sequence identity and structural homology with p53, and can engage p53-like tumor-suppressive programs. However, different pathways regulate p53 and p73, and p73 is not mutated in human tumors. Therefore, p73 represents a therapeutic target, and there is a critical need to understand genes and noncoding RNAs regulated by p73 and how they change during treatment regimens. Here, we define the p73 genomic binding profile and demonstrate its modulation by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) and inducer of p73. Rapamycin selectively increased p73 occupancy at a subset of its binding sites. In addition, multiple determinants of p73 binding, activity, and function were evident, and were modulated by mTOR. We generated an mTOR-p73 signature that is enriched for p73 target genes and miRNAs that are involved in mesenchymal differentiation and tumorigenesis, can classify rhabdomyosarcomas by clinical subtype, and can predict patient outcome.

MeSH Terms (13)

Cell Transformation, Neoplastic DNA-Binding Proteins Genome, Human Humans Mesoderm MicroRNAs Nuclear Proteins Protein Binding Rhabdomyosarcoma TOR Serine-Threonine Kinases Transcription, Genetic Tumor Protein p73 Tumor Suppressor Proteins

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