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The hormone-bound vitamin D receptor enhances the FBW7-dependent turnover of NF-?B subunits.

ABSTRACT: Signaling by hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D) has attracted increasing interest because of its non-classical actions, particularly its putative anticancer properties and its role in controlling immune system function. Notably, the hormone-bound vitamin D receptor (VDR) suppresses signaling by pro-inflammatory NF-?B transcription factors, although the underlying mechanisms have remained elusive. Recently, the VDR was shown to enhance the turnover of the oncogenic transcription factor cMYC mediated by the E3 ligase and tumor suppressor FBW7. As FBW7 also controls the turnover of the p100 (NF-?B2) subunit of the family, we determined whether the 1,25D enhanced FBW7-dependent turnover of NF-?B subunits p100, p105 (NF-?B1) and p65 (RELA). Protein levels of all three subunits declined markedly in the presence of 1,25D in multiple cell lines in the absence of substantial changes in mRNA expression. The VDR coimmunoprecipitated with all three subunits, and 1,25D treatment accelerated subunit turnover in cycloheximide-treated cells. Importantly, we observed an association of FBW7 with p105 and p65, as well as p100, and knockdown of FBW7 eliminated 1,25D-dependent subunit turnover. Moreover, expression of NF-?B target genes was elevated in FBW7-depleted cells. These results reveal that 1,25D signaling suppresses NF-?B function by enhancing FBW7-dependent subunit turnover.

SUBMITTER: Fekrmandi F

PROVIDER: S-EPMC4534774 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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The hormone-bound vitamin D receptor enhances the FBW7-dependent turnover of NF-κB subunits.

Fekrmandi Fatemeh F Wang Tian-Tian TT White John H JH

Scientific reports 20150813

Signaling by hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D) has attracted increasing interest because of its non-classical actions, particularly its putative anticancer properties and its role in controlling immune system function. Notably, the hormone-bound vitamin D receptor (VDR) suppresses signaling by pro-inflammatory NF-κB transcription factors, although the underlying mechanisms have remained elusive. Recently, the VDR was shown to enhance the turnover of the oncogenic transcription ...[more]

PMID: 26269414

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Project description:Since invasive bladder cancer (BC) is one of the most lethal urological malignant tumors worldwide, understanding the molecular mechanisms that trigger the migration, invasion, and metastasis of BC has great significance in reducing the mortality of this disease. Although RelA/p65, a member of the NF-kappa B transcription factor family, has been reported to be upregulated in human BCs, its regulation of BC motility and mechanisms have not been explored yet.NF-κBp65 expression was evaluated in N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced high invasive BCs by immunohistochemistry staining and in human BC cell lines demonstrated by Western Blot. The effects of NF-κBp65 knockdown on BC cell migration and invasion, as well as its regulated RhoGDIα and FBW7, were also evaluated in T24T cells by using loss- and gain-function approaches. Moreover, the interaction of FBW7 with RhoGDIα was determined with immunoprecipitation assay, while critical role of ubiquitination of RhoGDIα by FBW7 was also demonstrated in the studies.p65 protein was remarkably upregulated in the BBN-induced high invasive BCs and in human BC cell lines. We also observed that p65 overexpression promoted BC cell migration by inhibiting RhoGDIα expression. The regulatory effect of p65 on RhoGDIα expression is mediated by its upregulation of FBW7, which specifically interacted with RhoGDIα and promoted RhoGDIα ubiquitination and degradation. Mechanistic studies revealed that p65 stabilizing the E3 ligase FBW7 protein was mediated by its attenuating pten mRNA transcription.We demonstrate that p65 overexpression inhibits pten mRNA transcription, which stabilizes the protein expression of ubiquitin E3 ligase FBW7, in turn increasing the ubiquitination and degradation of RhoGDIα protein and finally promoting human BC migration. The novel identification of p65/PTEN/FBW7/RhoGDIα axis provides a significant insight into understanding the nature of BC migration, further offering a new theoretical support for cancer therapy.

Dataset Information

The hormone-bound vitamin D receptor enhances the FBW7-dependent turnover of NF-?B subunits.

Publications

The hormone-bound vitamin D receptor enhances the FBW7-dependent turnover of NF-κB subunits.

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