Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis.
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.
Department of Biochemistry, Center in Molecular Toxicology, and Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Jennifer M
JM
Rosenbluth
Deborah J
DJ
Mays
Aixiang
A
Jiang
Yu
Y
Shyr
Jennifer A
JA
Pietenpol
D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015894:Genome, Human; D006801:Humans; D008648:Mesoderm / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012208:Rhabdomyosarcoma / Q000145:classification / Q000235:genetics / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D058570:TOR Serine-Threonine Kinases
Mol Cell. 2006 Nov 17;24(4):593-602
17188034
Cancer Cell. 2006 Oct;10(4):281-93
17045206
Cold Spring Harb Perspect Biol. 2010 Aug;2(8):a000935
20679336
Cell Death Differ. 2006 Jun;13(6):962-72
16601753
Cancer Res. 2007 Apr 1;67(7):3431-40
17409454
Oncogene. 2008 Mar 27;27(14):2015-26
17922033
Nat Genet. 2006 Feb;38(2):228-33
16380711
Cell. 2008 Aug 8;134(3):521-33
18692474
Cancer Res. 2006 Jul 15;66(14):6936-46
16849537
Oncogene. 2007 Nov 15;26(52):7363-70
17563751
Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W551-4
16845068
Drug Resist Updat. 2008 Aug-Oct;11(4-5):152-63
18801697
J Biol Chem. 2002 Oct 18;277(42):40043-54
12171923
Cancer Lett. 2009 Jul 8;279(2):126-36
19008039
Cell Cycle. 2007 Aug 15;6(16):1995-2000
17721076
Nucleic Acids Res. 2008 Jun;36(11):3639-54
18474530
Cancer Res. 2008 Jun 1;68(11):4331-9
18519693
Nature. 2000 Mar 2;404(6773):99-103
10716451
Cancer Res. 2004 Aug 15;64(16):5539-45
15313887
PLoS One. 2010 Jul 14;5(7):e11572
20644729
Mol Cell Biol. 2008 Oct;28(19):5951-64
18678646
Cell. 2006 Jan 13;124(1):207-19
16413492