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.
Highlights
Hypoxia inducible factor 1 (HIF-1) is expressed ubiquitously in almost all mammalian cells
Our results proved that HIF-1α bound directly to the promoter of Mipu1 and promoted its expression under hypoxia condition mimicked by cobalt chloride (CoCl2)
Western blotting showed that CoCl2 increased expression of HIF-1α at protein level and its expression peaked at 12 h (Figure 1A)
Summary
Hypoxia inducible factor 1 (HIF-1) is expressed ubiquitously in almost all mammalian cells. HIF-1 is a heterodimer composed of an oxygen-labile α subunit and a constitutively expressed β subunit. The activity and subcellular localization of HIF-1α is oxygen-sensitive, increasing in response to hypoxia and decreasing under normoxia. The HIF-1β is not affected by hypoxia and is constitutively expressed in the nucleus. HIF-1α becomes stabilized, translocates from cytoplasm to nucleus and heterodimerizes with HIF-1β. The complex has transcriptional activity and binds to the hypoxia response elements (HREs) in the regulatory regions of the target genes to induce gene expression [1,2,3,4]
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