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Ubiquitination and Proteasomal Degradation of the BRCA1 Tumor Suppressor Is Regulated during Cell Cycle Progression
- Source :
- Journal of Biological Chemistry. 279:33909-33918
- Publication Year :
- 2004
- Publisher :
- Elsevier BV, 2004.
-
Abstract
- 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.
- Subjects :
- G2 Phase
Proteasome Endopeptidase Complex
endocrine system diseases
Recombinant Fusion Proteins
Ubiquitin-Protein Ligases
Mitosis
Biology
Transfection
Biochemistry
Cell Line
S Phase
chemistry.chemical_compound
Ubiquitin
Multienzyme Complexes
BARD1
Tumor Cells, Cultured
Humans
Protease Inhibitors
RNA, Messenger
Prometaphase
skin and connective tissue diseases
Molecular Biology
Regulation of gene expression
BRCA1 Protein
Nocodazole
Tumor Suppressor Proteins
Cell Cycle
G1 Phase
Cell Biology
Molecular biology
Cell biology
Cysteine Endopeptidases
Kinetics
Gene Expression Regulation
Urinary Bladder Neoplasms
chemistry
Cell culture
biology.protein
HeLa Cells
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 279
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....ed3af651e088d97fc2df900a760b0f8d