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The polyoma virus large T binding protein p150 is a transcriptional repressor of c-MYC.

ABSTRACT: p150, product of the SALL2 gene, is a binding partner of the polyoma virus large T antigen and a putative tumor suppressor. p150 binds to the nuclease hypersensitive element of the c-MYC promoter and represses c-MYC transcription. Overexpression of p150 in human ovarian surface epithelial cells leads to decreased expression, and downregulation to increased expression, of c-MYC. c-MYC is repressed upon restoration of p150 to ovarian carcinoma cells. Induction of apoptosis by etoposide results in recruitment of p150 to the c-MYC promoter and to repression of c-MYC. Analysis of data in The Cancer Genome Atlas shows negative correlations between SALL2 and c-MYC expression in four common solid tumor types.

SUBMITTER: Sung CK

PROVIDER: S-EPMC3460914 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The polyoma virus large T binding protein p150 is a transcriptional repressor of c-MYC.

Sung Chang Kyoo CK Yim Hyungshin H Gu Hongcang H Li Dawei D Andrews Erik E Duraisamy Sekhar S Li Cheng C Drapkin Ronny R Benjamin Thomas T

PloS one 20120928 9

p150, product of the SALL2 gene, is a binding partner of the polyoma virus large T antigen and a putative tumor suppressor. p150 binds to the nuclease hypersensitive element of the c-MYC promoter and represses c-MYC transcription. Overexpression of p150 in human ovarian surface epithelial cells leads to decreased expression, and downregulation to increased expression, of c-MYC. c-MYC is repressed upon restoration of p150 to ovarian carcinoma cells. Induction of apoptosis by etoposide results in ...[more]

PMID: 23029531

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Project description:α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

Dataset Information

The polyoma virus large T binding protein p150 is a transcriptional repressor of c-MYC.

Publications

The polyoma virus large T binding protein p150 is a transcriptional repressor of c-MYC.

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