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A role for the cyclin box in the ubiquitin-mediated degradation of cyclin G1.

ABSTRACT: Cyclin G1 was identified as a transcriptional target of p53 that encodes a protein with strong homology to the cyclin family of cell cycle regulators. We show that either ectopically expressed or endogenous cyclin G1 protein is very unstable, undergoes modification with ubiquitin, and is likely degraded by the proteasome. Ectopic cyclin G1 protein stability is increased by cyclin box mutation or by association with inactive cyclin-dependent kinase (CDK) subunits, suggesting that a function of cyclin G1 as a CDK regulator may be required for its rapid turnover. Furthermore, cyclin G1 and the cyclin box mutant interact with and are ubiquitinated by MDM2, another transcriptional target of p53 that acts as a negative regulator of p53 stability. These data suggest that the cyclin box has a role in the proteasome-mediated degradation of cyclin G1 and thus suggest a putative role for a CDK in cyclin G1 metabolism and function.

SUBMITTER: Piscopo DM

PROVIDER: S-EPMC2518098 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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A role for the cyclin box in the ubiquitin-mediated degradation of cyclin G1.

Piscopo Denise M DM Hinds Philip W PW

Cancer research 20080701 14

Cyclin G1 was identified as a transcriptional target of p53 that encodes a protein with strong homology to the cyclin family of cell cycle regulators. We show that either ectopically expressed or endogenous cyclin G1 protein is very unstable, undergoes modification with ubiquitin, and is likely degraded by the proteasome. Ectopic cyclin G1 protein stability is increased by cyclin box mutation or by association with inactive cyclin-dependent kinase (CDK) subunits, suggesting that a function of cy ...[more]

PMID: 18632610

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Project description:In response to DNA damage, eukaryotic cells initiate a complex signalling pathway, termed the DNA damage response (DDR), which coordinates cell cycle arrest with DNA repair. Studies have shown that oncogene-induced senescence, which provides a barrier to tumour development, involves activation of the DDR. Using a genome-wide RNA interference (RNAi) screen, we have identified 17 factors required for oncogenic BRAF to induce senescence in primary fibroblasts and melanocytes. One of these factors is an F-box protein, FBXO31, a candidate tumour suppressor encoded in 16q24.3, a region in which there is loss of heterozygosity in breast, ovarian, hepatocellular and prostate cancers. Here we study the cellular role of FBXO31, identify its target substrate and determine the basis for its growth inhibitory activity. We show that ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1, an important regulator of progression from G1 to S phase, resulting in arrest in G1. Cyclin D1 degradation results from a direct interaction with FBXO31 and is dependent on the F-box motif of FBXO31 and phosphorylation of cyclin D1 at Thr 286, which is known to be required for cyclin D1 proteolysis. The involvement of the DDR in oncogene-induced senescence prompted us to investigate the role of FBXO31 in DNA repair. We find that DNA damage induced by gamma-irradiation results in increased FBXO31 levels, which requires phosphorylation of FBXO31 by the DDR-initiating kinase ATM. RNAi-mediated knockdown of FBXO31 prevents cells from undergoing efficient arrest in G1 after gamma-irradiation and markedly increases sensitivity to DNA damage. Finally, we show that a variety of DNA damaging agents all result in a large increase in FBXO31 levels, indicating that induction of FBXO31 is a general response to genotoxic stress. Our results reveal FBXO31 as a regulator of the G1/S transition that is specifically required for DNA damage-induced growth arrest.

Dataset Information

A role for the cyclin box in the ubiquitin-mediated degradation of cyclin G1.

Publications

A role for the cyclin box in the ubiquitin-mediated degradation of cyclin G1.

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