Ubiquitin-mediated protein degradation and methylation-induced gene silencing cooperate in the inactivation of the INK4/ARF locus in Burkitt lymphoma cell lines.

Details

Serval ID
serval:BIB_2AC0148D537A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Ubiquitin-mediated protein degradation and methylation-induced gene silencing cooperate in the inactivation of the INK4/ARF locus in Burkitt lymphoma cell lines.
Journal
Cell Cycle
Author(s)
Roberti A., Rizzolio F., Lucchetti C., Leval L., Giordano A.
ISSN
1551-4005[electronic], 1551-4005[linking]
Publication state
Published
Issued date
2011
Volume
10
Number
1
Pages
127-134
Language
english
Abstract
Burkitt lymphoma is one of the most aggressive tumors affecting humans. Together with the characteristic chromosomal translocation that constitutively activates the c-Myc oncogene, alterations in cellular tumor suppressor pathways are additionally required in order to allow the cells to overcome anti-oncogenic barriers and proliferate in an uncontrolled manner. The INK4a/ARF locus on chromosome 9p21 is considered a safeguard locus since it encodes the two important tumor suppressor proteins, p14 (ARF) and p16 (INK4a) . By regulating the p53 and Rb pathways p14 (ARF) and p16 (INK4a) respectively act as pro-apoptotic and cell cycle inhibitor proteins. The importance of the INK4a/ARF locus has been well documented in several human tumors as well as in Burkitt lymphoma. Although the mechanisms responsible for the transcriptional regulation of the INK4a/ARF locus have been thoroughly characterized, less is known about its posttranscriptional control. In this study we found that p16 (INK4a) and p14 (Arf) are concurrently inactivated in a panel of BL cell lines. We demonstrate that along with the epigenetic silencing of the p16INK4a gene, the complete inactivation of the locus is achieved by the improper turnover of INK4/ARF proteins by the ubiquitin-proteasome system (UPS), as the proteasome inhibitor MG-132 blocks p14 (ARF) degradation and induces a dramatic stabilization of the p16 (INK4a ) protein. We establish that the simultaneous deregulation of both DNA methylation patterns and the ubiquitin-dependent proteolysis system is required to completely inactive the INK4/ARF locus, opening new prospects for the understanding and treatment of Burkitt lymphoma.
Pubmed
Web of science
Create date
04/02/2011 14:16
Last modification date
20/08/2019 13:10
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