Ubiquitination and proteasomal degradation of the BRCA1 tumor suppressor is regulated during cell cycle progression.

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.

• Authors: Atish D Choudhury, Hong Xu, Richard Baer
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 32 Pg. 33909-18 (Aug 06 2004) ISSN: 0021-9258 [Print] United States
• PMID: 15166217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BRCA1 Protein
• Multienzyme Complexes
• Protease Inhibitors
• RNA, Messenger
• Recombinant Fusion Proteins
• Tumor Suppressor Proteins
• Ubiquitin
• BARD1 protein, human
• Ubiquitin-Protein Ligases
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex
• Nocodazole

Topics

• 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