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Nat Cell Biol. 2015 Apr;17(4):511-23. doi: 10.1038/ncb3130. Epub 2015 Mar 16.

Hypoxia-inducible TAp73 supports tumorigenesis by regulating the angiogenic transcriptome.

Author information

1
Division of Cellular &Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
2
Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore.
3
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
4
Instituto de Biomedicina (IBIOMED), Campus Universitario, León 24071, Spain.
5
Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
6
Institute of Medical Biology, A-STAR, Singapore 138672, Singapore.
7
Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
8
1] Division of Cellular &Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore [3] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

Abstract

The functional significance of the overexpression of unmutated TAp73, a homologue of the tumour suppressor p53, in multiple human cancers is unclear, but raises the possibility of unidentified roles in promoting tumorigenesis. We show here that TAp73 is stabilized by hypoxia, a condition highly prevalent in tumours, through HIF-1α-mediated repression of the ubiquitin ligase Siah1, which targets TAp73 for degradation. Consequently, TAp73-deficient tumours are less vascular and reduced in size, and conversely, TAp73 overexpression leads to increased vasculature. Moreover, we show that TAp73 is a critical regulator of the angiogenic transcriptome and is sufficient to directly activate the expression of several angiogenic genes.  Finally, expression of TAp73 positively correlates with these angiogenic genes in several human tumours, and the angiogenic gene signature is sufficient to segregate the TAp73(Hi)- from TAp73(Low)-expressing tumours. These data demonstrate a pro-angiogenic role for TAp73 in supporting tumorigenesis, providing a rationale for its overexpression in cancers.

PMID:
25774835
DOI:
10.1038/ncb3130
[Indexed for MEDLINE]

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