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Carcinogenesis Advance Access originally published online on June 25, 2008
Carcinogenesis 2008 29(10):1878-1884; doi:10.1093/carcin/bgn150
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sp1 and p73 activate PUMA following serum starvation

Lihua Ming{dagger}, Tsukasa Sakaida{dagger}, Wen Yue, Anupma Jha, Lin Zhang and Jian Yu*

Departments of Pathology, and Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

* To whom correspondence should be addressed. University of Pittsburgh Cancer Institute, Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Tel: +412 623 7786; Fax: +1 412 623 7778; Email: yuj2{at}upmc.edu

p53-upregulated modulator of apoptosis (PUMA) plays an essential role in p53-dependent apoptosis following DNA damage. PUMA also mediates apoptosis independent of p53. In this study, we investigated the role and mechanism of PUMA induction in response to serum starvation in p53-deficient cancer cells. Following serum starvation, the binding of Sp1 to the PUMA promoter significantly increased, whereas inhibition of Sp1 completely abrogated PUMA induction. p73 was found to be upregulated by serum starvation and mediate PUMA induction through the p53-binding sites in the PUMA promoter. Sp1 and p73β appeared to cooperatively activate PUMA transcription, which is inhibited by the phosphoinsitide 3-kinase (PI3K)-protein kinase B (AKT) pathway. Furthermore, knockdown of PUMA suppressed serum starvation-induced apoptosis in leukemia cells. Our results suggest that transcription factors Sp1 and p73 mediate p53-independent induction of PUMA following serum starvation to trigger apoptosis in human cancer cells.

Abbreviations: AKT, protein kinase B; ChIP, chromatin immunoprecipitation; ERK, extracellular signal-regulated kinase; KO, knockout; PCR, polymerase chain reaction; PI3K, phosphoinsitide 3-kinase; PUMA, p53-upregulated modulator of apoptosis; siRNA, small interference RNA

{dagger} These authors contributed equally to this work.

Received March 28, 2008; revised June 5, 2008; accepted June 13, 2008.


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