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PMID:19046997

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Citation

Nardinocchi, L, Puca, R, Guidolin, D, Belloni, AS, Bossi, G, Michiels, C, Sacchi, A, Onisto, M and D'Orazi, G (2009) Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth. Biochim. Biophys. Acta 1793:368-77

Abstract

HIPK2 has been implicated in restraining tumor progression by more than one mechanism, involving both its catalytic and transcriptional co-repressor functions. Starting from the finding that HIPK2 knockdown by RNA-interference (HIPK2i) induced significant up-regulation of HIF-1alpha mRNA and of its target VEGF in tumor cells, we evaluated the role of HIPK2 in transcriptional regulation of HIF-1alpha. We found that HIPK2 overexpression downmodulated both HIF-1alpha reporter activity and mRNA levels and showed that HIPK2 was bound in vivo to the HIF-1alpha promoter likely in a multiprotein co-repressor complex with histone deacetylase 1 (HDAC1). Thus, the HIF-1alpha promoter was strongly acetylated following HIPK2 knockdown. The HIF-1alpha-dependent VEGF transcription was evaluated by co-transfection of a dominant negative (DN) construct of HIF-1alpha that inhibited VEGF reporter activity induced by HIPK2 knockdown. HIF-1alpha and VEGF up-regulation in HIPK2i cells correlated with increased vascularity of tumor xenografts in vivo and tube formation in HUVEC in vitro. These findings provide the first evidence of HIPK2-mediated transcriptional regulation of HIF-1alpha that might play a critical role in VEGF expression.

Links

PubMed Online version:10.1016/j.bbamcr.2008.10.013

Keywords

Animals; Carrier Proteins/metabolism; Cell Line, Tumor; Cell Proliferation; Chromatin Assembly and Disassembly/genetics; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Mice; Neoplasms/blood supply; Neoplasms/enzymology; Neoplasms/genetics; Neoplasms/pathology; Neovascularization, Pathologic/genetics; Promoter Regions, Genetic/genetics; Protein Binding; Protein-Serine-Threonine Kinases/deficiency; Protein-Serine-Threonine Kinases/metabolism; Repressor Proteins/metabolism; Transcription, Genetic; Vascular Endothelial Growth Factor A/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HIPK2

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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