Hypoxia-inducible factor 1 alpha is regulated by RBM38, a RNA-binding protein and a p53 family target, via mRNA translation
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Seong-Jun Cho1,*, I-Fang Teng1,*, Min Zhang1, Tiffany Yin1, Yong-Sam Jung1, Jin Zhang1 and Xinbin Chen1
1 Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA
* These authors contributed equally to this work
Xinbin Chen, email:
Keywords: p53, RBM38, RNPC1, HIF1α, mRNA translation
Received: September 10, 2014 Accepted: November 15, 2014 Published: November 16, 2014
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.
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