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Published on: July 8, 2020
Survivin repression by p53, Rb and E2F2 in normal human melanocytes
Deepak Raj1, Tong Liu, George Samadashwily
1Department of Dermatology, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA.
Carcinogenesis
|October 6, 2007
Summary
Normal melanocytes use p53 and retinoblastoma (Rb) to suppress survivin. Loss of these tumor suppressors during melanoma development allows survivin to promote cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Survivin, an inhibitor of apoptosis protein, is crucial for cell cycle progression and highly expressed in cancers like melanoma.
- Previous studies show survivin is upregulated in melanoma, essential for cell viability, and linked to UV-induced melanoma and metastasis.
- The precise mechanisms regulating survivin expression in normal melanocytes versus melanoma remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms controlling survivin transcription in normal melanocytes.
- To identify key regulators involved in survivin's repression in normal melanocytes and its upregulation during melanoma development.
Main Methods:
- Analysis of survivin promoter activity in normal human melanocytes.
- Investigation of the roles of p53 and retinoblastoma (Rb) proteins in survivin regulation.
- Electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) to assess protein-DNA interactions.
- Site-directed mutagenesis of the survivin promoter to evaluate the impact of p53 and E2F binding sites.
Main Results:
- Basal levels of p53 and Rb are essential for repressing survivin transcription in normal melanocytes, independent of external stimuli.
- Survivin repression is not mediated by changes in protein stability or promoter methylation.
- p53 and Rb directly bind to the survivin promoter, with p53 also influencing survivin via p21 activation.
- E2F2 plays a novel role in the negative regulation of survivin.
- A new E2F-binding site was identified in the survivin promoter; mutations in p53 or E2F binding sites increased promoter activity.
Conclusions:
- The p53 and Rb tumor suppressor pathways are critical for maintaining low survivin expression in normal melanocytes.
- Disruption of either the p53 or Rb pathways during melanocyte transformation contributes to survivin upregulation in melanoma.
- These findings highlight a crucial mechanism linking common genetic alterations in melanoma to the expression of a key oncogenic protein.
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