Carcinogenesis Advance Access originally published online on October 4, 2007
Carcinogenesis 2008 29(1):194-201; doi:10.1093/carcin/bgm219
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Survivin repression by p53, Rb and E2F2 in normal human melanocytes
1 Department of Dermatology, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA
2 Department of Oncological Sciences
3 Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
4 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
* To whom correspondence should be addressed. Tel: +1 801 581 4682; Fax: +1 801 585 0900; Email: doug.grossman{at}hci.utah.edu
The inhibitor of apoptosis protein survivin is a dual mediator of apoptosis resistance and cell cycle progression and is highly expressed in cancer. We have shown previously that survivin is up-regulated in melanoma compared with normal melanocytes, is required for melanoma cell viability, and that melanocyte expression of survivin predisposes mice to ultraviolet-induced melanoma and metastasis. The mechanism of survivin up-regulation in the course of melanocyte transformation and its repression in normal melanocytes, however, has not been clearly defined. We show here that p53 and retinoblastoma (Rb), at basal levels and in the absence of any activating stimuli, are both required to repress survivin transcription in normal human melanocytes. Survivin repression in melanocytes does not involve alterations in protein stability or promoter methylation. p53 and Rb (via E2Fs) regulate survivin expression by direct binding to the survivin promoter; p53 also affects survivin expression by activating p21. We demonstrate a novel role for E2F2 in the negative regulation of survivin expression. In addition, we identify a novel E2F-binding site in the survivin promoter and show that mutation of either the p53- or E2F-binding sites is sufficient to increase promoter activity. These studies suggest that compromise of either p53 or Rb pathways during melanocyte transformation leads to up-regulation of survivin expression in melanoma.
Abbreviations: DTT, dithiothreitol; EDTA, ethylenediaminetetraacetic acid; HEPES, 4-2-hydroxyethyl-1-piperazineethanesulfonic acid; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; Rb, retinoblastoma; siRNA, small interfering RNA; RNAi, RNA interference
Received July 24, 2007; revised September 17, 2007; accepted September 23, 2007.
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