IKK-?/NF-?B p65 mediates p27(Kip1) protein degradation in arsenite response.

ABSTRACT: p27(Kip1) is a potent inhibitor of the cyclin-dependent kinases that drive G1 to S phase transition. Since deregulation of p27(Kip1) is found in many malignancies and is associated with the poor prognosis, elucidation of the molecular bases for regulation of p27(Kip1) expression is of great significance, not only in providing insight into the understanding of biological p27(Kip1), but also in the development of new cancer therapeutic tactics. We here explored the inhibitory regulation of IKK? on p27(Kip1) expression following arsenite exposure. We found that although the basal level of p27(Kip1) expression in the IKK?(-/-) cells is much lower than that in the IKK?(+/+) cells, the deletion of IKK? in the MEFs led to a marked increase in p27(Kip1) protein induction due to arsenite exposure in comparison to that in the IKK?(+/+) cells. The IKK? regulatory effect on p27(Kip1) expression was also verified in the IKK?(-/-) and IKK?(-/-) cells with IKK? reconstitutional expression, IKK?(-/-) (IKK?). Further studies indicated that IKK?-mediated p27(Kip1) downregulation occurred at protein degradation level via p65-dependent and p50-independent manner. Moreover, the results obtained from the comparison of arsenite-induced GSK3? activation among transfectants of WT, IKK?(-/-) and IKK?(-/-) (IKK?), and the utilization of GSK? shRNA, demonstrated that IKK? regulation of p27 protein degradation was mediated by GSK3? following arsenite exposure.

SUBMITTER: Guo W 

PROVIDER: S-EPMC4076889 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature