Mipu1, a novel direct target gene, is involved in hypoxia inducible factor 1-mediated cytoprotection

PLoS One. 2013 Dec 11;8(12):e82827. doi: 10.1371/journal.pone.0082827. eCollection 2013.

Abstract

Mipu1 (myocardial ischemic preconditioning up-regulated protein 1), recently identified in our lab, is a novel zinc-finger transcription factor which is up-regulated during ischemic preconditioning. However, it is not clear what transcription factor contributes to its inducible expression. In the present study, we reported that HIF-1 regulates the inducible expression of Mipu1 which is involved in the cytoprotection of HIF-1α against oxidative stress by inhibiting Bax expression. Our results showed that the inducible expression of Mipu1 was associated with the expression and activation of transcription factor HIF-1 as indicated by cobalt chloride (CoCl2) treatment, HIF-1α overexpression and knockdown assays. EMSA and luciferase reporter gene assays showed that HIF-1α bound to the hypoxia response element (HRE) within Mipu1 promoter region and promoted its transcription. Moreover, our results revealed that Mipu1 inhibited the expression of Bax, an important pro-apoptosis protein associated with the intrinsic pathway of apoptosis, elevating the cytoprotection of HIF-1 against hydrogen peroxide (H2O2)-mediated injury in H9C2 cells. Our findings implied that Bax may be a potential target gene of transcription factor Mipu1, and provided a novel insight for understanding the cytoprotection of HIF-1 and new clues for further elucidating the mechanisms by which Mipu1 protects cell against pathological stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cobalt / pharmacology
  • Gene Expression
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Hypoxia / metabolism*
  • Hypoxia / microbiology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oxidative Stress
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • Rats
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Transcriptional Activation
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mipu1 protein, rat
  • Nuclear Proteins
  • Repressor Proteins
  • bcl-2-Associated X Protein
  • Cobalt
  • cobaltous chloride

Grants and funding

This work was supported partially by the following grants: the Major National Basic Research Program of China (2007CB512007 for X.X. and K.W.) and the National Natural Science Foundation of China (30770855 for X.X.; 30971205 for L.J.; 81270201 for K.W.) and the Hunan province Nature Science Foundation (11JJ2047 for K.W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.