Hypoxia-inducible factor 1 alpha is regulated by RBM38, a RNA-binding protein and a p53 family target, via mRNA translation

Seong-Jun Cho,Xinbin Chen,Yong-Sam Jung,Tiffany Yin,Min Zhang,Jin Zhang,I-Fang Teng

doi:10.18632/oncotarget.2786

Seong-Jun Cho, Xinbin Chen + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.2786

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Journal: Oncotarget	Publication Date: Nov 16, 2014
Citations: 43	License type: cc-by

Affiliation: University of California, Davis

Abstract

Hypoxia-inducible factor 1 (HIF1), a heterodimeric transcription factor, consists of HIF1α and HIF1β and is necessary for cell growth and survival under a hypoxic condition. Thus, the level and activity of HIF1α needs to be tightly controlled. Indeed, HIF1α protein stability is controlled by prolyl hydroxylase and von Hippel-Lindau-mediated proteosomal degradation. However, it remains unclear whether HIF1α expression is controlled by other pathways. Here, we showed that RNA-binding protein RBM38, a target of the p53 family, regulates HIF1α expression via mRNA translation. Specifically, we showed that under a hypoxic condition, ectopic expression of RBM38 decreased, whereas knockdown of RBM38 increased, the level of HIF1α protein. We also showed that the rate of de novo HIF1α protein synthesis was increased by knockdown of RBM38. Additionally, we showed that RBM38 directly bound to HIF1α 5' and 3'UTRs. Consistently, we showed that the rate of mRNA translation for a heterologous reporter that carries HIF1α 5'and/or 3'UTRs was increased upon knockdown of RBM38. Furthermore, we showed that knockdown of RBM38 increased, whereas ectopic expression of RBM38 decreased, the binding of eIF4E to HIF1α mRNA. Together, our data suggest that RBM38 is a novel translational regulator of HIF1α under a hypoxic condition.

Highlights

Hypoxia induces an array of cellular processes to maintain ATP production via glycolysis and other survival pathways [1, 2]
Www.impactjournals.com/oncotarget a long 3’UTR along with an AU-rich element (ARE), we examined whether HIF1α expression is modulated by RNA-binding protein RBM38, a target of the p53 family and a potent regulator of multiple pro-survival and prodeath factors [7,8,9,10,11,12,13]
We showed that the level of HIF1α protein was decreased by RBM38 in HCT116 cells treated with CoCl2, a hypoxia mimetic (Fig. 1A)

Summary

INTRODUCTION

Hypoxia (low oxygen tension) induces an array of cellular processes to maintain ATP production via glycolysis and other survival pathways [1, 2]. In response to high levels of oxygen, HIF1α protein is modified by prolyl hydroxylase and rapidly degraded through the VHL-mediated proteasomal pathway [1]. Once normoxia turns into hypoxia, prolyl hydroxylase is inactivated and subsequently, HIF1α is rapidly stabilized through decreased degradation [3]. HIF1α induces an array of target genes associated with cell survival (insulin-like growth factor-binding protein-1, Nip3), angiogenesis RBM38 is known to regulate mRNA translation of p53 and mRNA stability of p21, HuR, p63, p73, MDM2, and MIC-1 transcripts [7,8,9,10,11,12,13]. We found that knockdown of RBM38 enhanced HIF1α mRNA translation via binding to HIF1α 5′ and 3′UTRs. Together, we uncovered a novel mechanism by which HIF1α is regulated by the p53 pathway via RBM38

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES