Document Detail


Ubiquitination and proteasomal degradation of the BRCA1 tumor suppressor is regulated during cell cycle progression.
MedLine Citation:
PMID:  15166217     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The BRCA1 tumor suppressor and the BARD1 protein form a stable heterodimeric complex that can catalyze the formation of polyubiquitin chains. Expression of BRCA1 fluctuates in a cell cycle-dependent manner, such that low steady-state levels of BRCA1 gene products are found in resting cells and early G1 cycling cells and high levels in S and G2 phase cells. Although transcriptional activation of the BRCA1 gene can account for induction of BRCA1 expression at the G1/S transition, the mechanisms by which BRCA1 is down-regulated during cell cycle progression have not been addressed. Here we show that the steady-state levels of BRCA1 protein remain elevated throughout mitosis but begin to decline at the M/G1 transition. This decline in BRCA1 levels coincides with the appearance of proteasome-sensitive ubiquitin conjugates of BRCA1 at the onset of G1. Formation of these conjugates occurs throughout G1 and S, but not in cells arrested in prometaphase by nocodazole. The proteasome-sensitive ubiquitin conjugates of BRCA1 appear to be distinct from BRCA1 autoubiquitination products and are probably catalyzed by the action of other cellular E3 ligases. Interestingly, co-expression of BARD1 inhibits the formation of these conjugates, suggesting that BARD1 serves to stabilize BRCA1 expression in part by reducing proteasome-sensitive ubiquitination of BRCA1 polypeptides. In summary, these data indicate that the cell cycle-dependent pattern of BRCA1 expression is determined in part by ubiquitin-dependent proteasomal degradation.
Authors:
Atish D Choudhury; Hong Xu; Richard Baer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-05-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  279     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-08-02     Completed Date:  2004-10-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33909-18     Citation Subset:  IM    
Affiliation:
Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, New York 10032, USA.
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MeSH Terms
Descriptor/Qualifier:
BRCA1 Protein / analysis,  genetics*,  metabolism*
Cell Cycle / physiology*
Cell Line
Cysteine Endopeptidases / metabolism*
G1 Phase
G2 Phase
Gene Expression Regulation*
Hela Cells
Humans
Kinetics
Mitosis
Multienzyme Complexes / antagonists & inhibitors,  metabolism*
Nocodazole / pharmacology
Protease Inhibitors / pharmacology
Proteasome Endopeptidase Complex
RNA, Messenger / analysis
Recombinant Fusion Proteins
S Phase
Transfection
Tumor Cells, Cultured
Tumor Suppressor Proteins / analysis,  genetics,  metabolism
Ubiquitin / metabolism*
Ubiquitin-Protein Ligases / analysis,  genetics,  metabolism
Urinary Bladder Neoplasms
Grant Support
ID/Acronym/Agency:
CA97403/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/BARD1 protein, human; 0/BRCA1 Protein; 0/Multienzyme Complexes; 0/Protease Inhibitors; 0/RNA, Messenger; 0/Recombinant Fusion Proteins; 0/Tumor Suppressor Proteins; 0/Ubiquitin; 31430-18-9/Nocodazole; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 6.3.2.19/Ubiquitin-Protein Ligases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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