Letter abstract
Nature Cell Biology 9, 698 - 706 (2007)
Published online: 13 May 2007 | doi:10.1038/ncb1598
p73 supports cellular growth through c-Jun-dependent AP-1 transactivation
Faina Vikhanskaya1, Wen Hong Toh1, Iqbal Dulloo1, Qiang Wu2, Lakshmanane Boominathan3, Huck Hui Ng4,2, Karen H. Vousden5 & Kanaga Sabapathy1,6
The cause or consequence of overexpression of p73 (refs 1, 2), the structural and functional homologue of the tumour-suppressor gene product p53 (refs 3, 4), in human cancers is poorly understood. Here, we report a role for p73 in supporting cellular growth through the upregulation of AP-1 transcriptional activity. p73 suppresses growth when overexpressed alone, but synergises with the proto-oncogene c-Jun to promote cellular survival. Conversely, silencing of p73 expression compromises cellular proliferation. Molecular analysis revealed that expression of the AP-1 target-gene product cyclinD1 (ref. 5) is reduced concomitant with p73, but not p53, silencing. Moreover, cyclinD1 was induced by p73 expression in a c-Jun-dependent manner, and was required for p73-mediated cell survival. Furthermore, c-Jun-dependent AP-1 transcriptional activity was augmented by p73 and, consistently, induction of endogenous AP-1 target genes was compromised in the absence of p73. Chromatin immunoprecipitation and electrophoretic mobility shift analysis indicated that p73 enhanced the binding of phosphorylated c-Jun and Fra-1, another AP-1 family member, to AP-1 consensus DNA sequences, by regulating c-Jun phosphorylation and Fra-1 expression. Collectively, our data demonstrates a novel and unexpected role of p73 in augmenting AP-1 transcriptional activity through which it supports cellular growth.
- Laboratory of Molecular Carcinogenesis, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
- Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore.
- Department of Physiology, National University of Singapore, 10, Kent Ridge Crescent, Singapore 119260, Singapore.
- Department of Biological Sciences, National University of Singapore, 10, Kent Ridge Crescent, Singapore 119260, Singapore.
- Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
- Department of Biochemistry, National University of Singapore, 10, Kent Ridge Crescent, Singapore 119260, Singapore.
Correspondence to: Kanaga Sabapathy1,6 e-mail: cmrksb@nccs.com.sg
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