Journal
ONCOGENE
Volume 29, Issue 10, Pages 1498-1508Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.424
Keywords
ING3; protein degradation; Skp2; cell cycle; apoptosis
Funding
- Cancer Research Society
- Canadian Institutes of Health Research [MOP-93810]
- Canadian Dermatology Foundation
- Michael Smith Foundation for Health Research
- University of British Columbia
- National Cancer Institute of Canada
Ask authors/readers for more resources
The inhibitor of growth family member 3 (ING3) has been shown to modulate transcription, cell cycle control and apoptosis. We previously reported that nuclear ING3 expression was remarkably reduced in melanomas, which correlated with a poorer patient survival, suggesting that decreased ING3 expression may be associated with melanoma progression. However, the mechanism of diminished ING3 expression in melanoma is not clear. Here we show that ING3 level was decreased in metastatic melanoma cells because of a rapid degradation. Furthermore, we showed that ING3 undergoes degradation through the ubiquitin proteasome pathway. ING3 physically interacts with subunits of E3 ligase Skp1-Cullin-F-box protein complex (SCF complex). Knockdown of F-box protein S-phase kinase-associated protein 2 (Skp2) reduces the ubiquitination of ING3 and significantly stabilizes ING3 in melanoma cells. In addition, lysine 96 residue is essential for ING3 ubiquitination as its mutation to arginine dramatically abrogated ING3 degradation. Disruption of ING3 degradation stimulated ING3-induced G1 cell-cycle arrest and enhanced ultraviolet-induced apoptosis. Taken together, our data show that ING3 is degraded by the ubiquitin-proteasome pathway through the SCFSkp2 complex and interruption of ING3 degradation enhances the tumor-suppressive function of ING3, which provides a potential cancer therapeutic approach by interfering ING3 degradation. Oncogene (2010) 29, 1498-1508; doi:10.1038/onc.2009.424; published online 23 November 2009
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available