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The RNA helicase p68 modulates expression and function of the ?133 isoform(s) of p53, and is inversely associated with ?133p53 expression in breast cancer.

ABSTRACT: The RNA helicase p68 is a potent co-activator of p53-dependent transcription in response to DNA damage. Previous independent studies have indicated that p68 and the ?133p53 isoforms, which modulate the function of full-length p53, are aberrantly expressed in breast cancers. Here we identify a striking inverse association of p68 and ?133p53 expression in primary breast cancers. Consistent with these findings, small interfering RNA depletion of p68 in cell lines results in a p53-dependant increase of ?133p53 in response to DNA damage, suggesting that increased ?133p53 expression could result from downregulation of p68 and provide a potential mechanistic explanation for our observations in breast cancer. ?133p53?, which has been shown to negatively regulate the function of full-length p53, reciprocally inhibits the ability of p68 to stimulate p53-dependent transcription from the p21 promoter, suggesting that ?133p53? may be competing with p68 to regulate p53 function. This hypothesis is underscored by our observations that p68 interacts with the C-terminal domain of p53, co-immunoprecipitates 133p53? from cell extracts and interacts only with p53?molecules that are able to form tetramers. These data suggest that p68, p53 and 133p53? may form part of a complex feedback mechanism to regulate the expression of ?133p53, with consequent modification of p53-mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild-type p53.

SUBMITTER: Moore HC

PROVIDER: S-EPMC3016604 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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The RNA helicase p68 modulates expression and function of the Δ133 isoform(s) of p53, and is inversely associated with Δ133p53 expression in breast cancer.

Moore H C HC Jordan L B LB Bray S E SE Baker L L Quinlan P R PR Purdie C A CA Thompson A M AM Bourdon J-C JC Fuller-Pace F V FV

Oncogene 20100906 49

The RNA helicase p68 is a potent co-activator of p53-dependent transcription in response to DNA damage. Previous independent studies have indicated that p68 and the Δ133p53 isoforms, which modulate the function of full-length p53, are aberrantly expressed in breast cancers. Here we identify a striking inverse association of p68 and Δ133p53 expression in primary breast cancers. Consistent with these findings, small interfering RNA depletion of p68 in cell lines results in a p53-dependant increase ...[more]

PMID: 20818423

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Project description:BackgroundRelA/p65 a crucial member of NF-?B signaling pathway plays diverse role in mediating oncogenesis. Limited knowledge prevails on the mechanistic insights of RelA gene regulation. RNA helicase p68 apart from being a vital player of RNA metabolism acts as a transcriptional coactivator of several oncogenic transcription factors including ?-catenin and is highly implicated in cancer progression. In this study, we aim to discern the molecular mechanism of how an RNA helicase, p68 deploys a major oncogenic signaling pathway, Wnt/ ?-catenin to regulate the expression of RelA, an indispensable component of NF-?B signaling pathway towards driving colon carcinogenesis.MethodsImmunoblotting and quantitative RT-PCR was performed for determining the protein and mRNA expressions of the concerned genes respectively. Luciferase assay was employed for studying the promoter activity of RelA. Chromatin immunoprecipitation was used to evaluate the occupancy of transcription factors on the RelA promoter. Immunohistochemical analysis was conducted using FFPE sections derived from normal human colon and colon cancer patient samples. Finally, a syngeneic colorectal allograft mouse model was used to assess physiological significance of the in vitro findings.Resultsp68, ?-catenin and RelA proteins were found to bear strong positive correlation in normal and colon carcinoma patient samples. Both p68 and ?-catenin increased RelA mRNA and protein expression. p68, ?-catenin and Wnt3a elevated RelA promoter activity. Conversely, p68 and ?-catenin knockdown diminished RelA promoter activity and led to reduced RelA mRNA and protein expression. p68 was perceived to occupy RelA promoter with ?-catenin at the TCF4/LEF (TBE) sites thereby potentiating RelA transcription. p68 and ?-catenin alliance positively modulated the expression of signature NF-?B target genes. Enhanced NF-?B target gene expression by p68 was corroborated by findings in clinical samples. Tumors generated in mice colorectal allograft model, stably expressing p68 further reinforced our in vitro findings.ConclusionsWe report for the first time a novel mechanism of alliance between p68 and ?-catenin in regulating the expression of RelA and stimulating the NF-?B signaling axis towards driving colon carcinogenesis. This study unravels novel modes of p68-mediated colon carcinogenesis, marking it a potential target for therapy.

Dataset Information

The RNA helicase p68 modulates expression and function of the ?133 isoform(s) of p53, and is inversely associated with ?133p53 expression in breast cancer.

Publications

The RNA helicase p68 modulates expression and function of the Δ133 isoform(s) of p53, and is inversely associated with Δ133p53 expression in breast cancer.

Similar Datasets

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