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Biochem Biophys Res Commun. 2014 May 16;447(4):563-8. doi: 10.1016/j.bbrc.2014.04.055. Epub 2014 Apr 18.

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

Author information

  • 1Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States; Pathology Department, Wuhan University, 185 Donghu Rd., Wuhan, Hubei 430071, China.
  • 2Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States.
  • 3Physiology Department, Wuhan University, 185 Donghu Rd., Wuhan, Hubei 430071, China.
  • 4Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States. Electronic address: chuanshu.huang@nyumc.org.

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 IKKβ on p27(Kip1) expression following arsenite exposure. We found that although the basal level of p27(Kip1) expression in the IKKβ(-/-) cells is much lower than that in the IKKβ(+/+) cells, the deletion of IKKβ in the MEFs led to a marked increase in p27(Kip1) protein induction due to arsenite exposure in comparison to that in the IKKβ(+/+) cells. The IKKβ regulatory effect on p27(Kip1) expression was also verified in the IKKβ(-/-) and IKKβ(-/-) cells with IKKβ reconstitutional expression, IKKβ(-/-) (IKKβ). Further studies indicated that IKKβ-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 GSK3β activation among transfectants of WT, IKKβ(-/-) and IKKβ(-/-) (IKKβ), and the utilization of GSKβ shRNA, demonstrated that IKKβ regulation of p27 protein degradation was mediated by GSK3β following arsenite exposure.

KEYWORDS:

Arsenite; GSK; IKKβ; NF-κB; p27(Kip1) protein degradation

PMID:
24751519
PMCID:
PMC4076889
DOI:
10.1016/j.bbrc.2014.04.055
[PubMed - indexed for MEDLINE]
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