Differentiation-related gene-1 decreases Bim stability by proteasome-mediated degradation Journal Article

   

Authors:	Ambrosini, G.; Seelman, S. L.; Schwartz, G. K.
Article Title:	Differentiation-related gene-1 decreases Bim stability by proteasome-mediated degradation
Abstract:	Drg1 was identified as a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. Its expression is associated with resistance to irinotecan (CPT-11) therapy in preclinical colorectal cancer models both in vitro and in vivo. However, the functional significance of Drg1 in these processes is unknown. We have shown for the first time that Drg1 directly binds to the BH3-only proapoptotic protein Bim. Depletion of Drg1 by small interfering RNA induced up-regulation of Bim and its accumulation in the mitochondria, which correlated with loss of mitochondrial membrane potential and induction of apoptosis in cells exposed to SN-38. Further analyses revealed that Drg1 promotes degradation of Bim through the Cullin2/ ElonginB-CIS ubiquitin-protein ligase complex. Conversely, in the absence of Drg1, Bim was stabilized and bound more abundantly to Hsp70. These results show that Drg1 renders cancer cells more resistant to chemotherapy through enhanced proteasome-mediated Bim degradation. ©2009 American Association for Cancer Research.
Keywords:	controlled study; unclassified drug; human cell; proto-oncogene proteins; protein function; protein analysis; apoptosis; proteasome; proteasome endopeptidase complex; ubiquitin protein ligase; protein degradation; protein protein interaction; 7 ethyl 10 hydroxycamptothecin; bim protein; cullin 2; elongin b; protein; protein drg1; small interfering rna; mitochondrial membrane potential; protein binding; protein stability; antineoplastic agents, phytogenic; apoptosis regulatory proteins; camptothecin; colonic neoplasms; dna, antisense; down-regulation; gtp-binding proteins; hct116 cells; membrane proteins; rna, small interfering
Journal Title:	Cancer Research
Volume:	69
Issue:	15
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2009-08-01
Start Page:	6115
End Page:	6121
Language:	English
DOI:	10.1158/0008-5472.can-08-3024
PUBMED:	19622774
PROVIDER:	scopus
PMCID:	PMC2733857
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-68049123430&partnerID=40&md5=74bb31a239660bcb5f386ce59ec7632c
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/43