Title

Antidicer RNAse activity of monocyte chemotactic protein-induced protein-1 is critical for inducing angiogenesis

Authors

Authors

A. Roy; M. J. Zhang; Y. Saad;P. E. Kolattukudy

Comments

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Abbreviated Journal Title

Am. J. Physiol.-Cell Physiol.

Keywords

MCPIP1; HIF-1 alpha; SIRT-1; miR-20b; miR-34a; NF-KAPPA-B; ENDOTHELIAL GROWTH-FACTOR; ENDOPLASMIC-RETICULUM STRESS; TUMOR-SUPPRESSOR PROTEIN; CELL-SURVIVAL; TRANSCRIPTION FACTOR; SIRT1; DEACETYLASE; MESSENGER-RNA; DEPENDENT REGULATION; OXIDATIVE STRESS; Cell Biology; Physiology

Abstract

Inflammatory angiogenesis involves the induction of a novel gene ZC3H12A encoding monocyte chemoattractant protein-1 (MCP-1)-induced protein-1 (MCPIP1) that has deubiquitinase and antidicer RNAse activities. If and how these enzymatic activities of MCPIP1 mediate the biological functions of MCPIP1 are unknown. Present studies with human umbilical vein endothelial cells suggest that MCPIP-induced angiogenesis is mediated via hypoxia-inducible factor (HIF-1 alpha), vascular endothelial growth factor (VEGF), and silent information regulator (SIRT-1) induction that results in the inhibition of angiogenesis inhibitor thrombospondin-1. MCPIP1 expression inhibited the production of the antiangiogenic microRNA (miR)-20b and -34a that repress the translation of HIF-1 alpha and SIRT-1, respectively. The RNase-dead MCPIP mutant D141N not only did not induce angiogenesis but also failed to inhibit the production of miR-20b and -34a suggesting that the antidicer RNase activity of MCPIP1 is involved in MCPIP-mediated angiogenesis. Mimetics of miR-20b and -34a inhibited MCPIP1-induced angiogenesis confirming that MCPIP1 suppresses the biogenesis of miR-20b and -34a. Furthermore, our results indicate that MCPIP expression induces nuclear translocation of HIF-1 alpha. We show that under hypoxia angiogenesis is mediated via induction of MCPIP1 and under normoxia, in vitro, MCPIP deubiquitinates ubiquitinated HIF-1 alpha and the stabilized HIF-1 alpha enters the nucleus to promote the transcription of its target genes, cyclooxygenase-2 and VEGF, suggesting that the deubiquitinase activity of MCPIP may also promote angiogenesis. The present results show for the first time that the antidicer RNase activity of MCPIP1 is critical in mediating a biological function of MCPIP, namely angiogenesis.

Journal Title

American Journal of Physiology-Cell Physiology

Volume

305

Issue/Number

10

Publication Date

1-1-2013

Document Type

Article

Language

English

First Page

C1021

Last Page

C1032

WOS Identifier

WOS:000327391700004

ISSN

0363-6143

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