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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
32
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pubmed:dateCreated |
2004-8-2
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/BARD1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/BRCA1 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Nocodazole,
http://linkedlifedata.com/resource/pubmed/chemical/Protease Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin-Protein Ligases
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
6
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
33909-18
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:15166217-BRCA1 Protein,
pubmed-meshheading:15166217-Cell Cycle,
pubmed-meshheading:15166217-Cell Line,
pubmed-meshheading:15166217-Cysteine Endopeptidases,
pubmed-meshheading:15166217-G1 Phase,
pubmed-meshheading:15166217-G2 Phase,
pubmed-meshheading:15166217-Gene Expression Regulation,
pubmed-meshheading:15166217-HeLa Cells,
pubmed-meshheading:15166217-Humans,
pubmed-meshheading:15166217-Kinetics,
pubmed-meshheading:15166217-Mitosis,
pubmed-meshheading:15166217-Multienzyme Complexes,
pubmed-meshheading:15166217-Nocodazole,
pubmed-meshheading:15166217-Protease Inhibitors,
pubmed-meshheading:15166217-Proteasome Endopeptidase Complex,
pubmed-meshheading:15166217-RNA, Messenger,
pubmed-meshheading:15166217-Recombinant Fusion Proteins,
pubmed-meshheading:15166217-S Phase,
pubmed-meshheading:15166217-Transfection,
pubmed-meshheading:15166217-Tumor Cells, Cultured,
pubmed-meshheading:15166217-Tumor Suppressor Proteins,
pubmed-meshheading:15166217-Ubiquitin,
pubmed-meshheading:15166217-Ubiquitin-Protein Ligases,
pubmed-meshheading:15166217-Urinary Bladder Neoplasms
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pubmed:year |
2004
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pubmed:articleTitle |
Ubiquitination and proteasomal degradation of the BRCA1 tumor suppressor is regulated during cell cycle progression.
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pubmed:affiliation |
Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, New York 10032, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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