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

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.

The RNA-Protein Interactome of Differentiated Kidney Tubular Epithelial Cells

“…36 A very interesting example of the potential role of RNA-protein interaction in the response to hypoxia is the targeting of specific mRNAs to polysomes for translation via the 59 cap binding of the HIF2a-RBM4-eIF4E2 complex. 37,38 Furthermore, key aspects regarding hypoxia are cellular metabolic adaptations (e.g., activation of glycolysis) and recent work has suggested that a large number of metabolic enzymes possess RNAbinding capacity. 2,3 Interestingly, a significant number of enzymes involved primarily in glucose handling in the kidney were identified as RBPs either by our RIC screen or previously published data 3 (Supplemental Figure 5A).…”

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

“…RBPs like Y‐box binding protein 1 (YB‐1) , Hu antigen R (HuR) , polypyrimidine tract binding protein (PTB) , and cold‐inducible RBP (CIRBP) are able to increase the stability of the HIF1α mRNA followed by elevated protein synthesis. On the other hand, tristetraprolin (TTP) RBP family , RNA binding motif protein 38 (RBM38) , and cytoplasmic polyadenylation element binding proteins 1 and 2 (CPEB1 and CPEB2) bind to the 3′ UTR of the HIF1A mRNA leading to decreased translation. In the 5′ UTR of the HIF2A mRNA, iron‐responsive elements (IREs) are present.…”

Comparative genomic investigation of high-elevation adaptation in ectothermic snakes

“…When DNA has sustained damage, p53 expression can be stimulated and then can activate DNA repair proteins, including MSH2 (21), ERCC6 (22), RBM38 (23), and p21 (24) (Fig. 2B).…”

“…RBM38 is a target of p53 and a negative regulator of p53 and MDM2 (26). Interestingly, RBM38 is required for maintaining the stability of the basal and stress-induced p21 transcript (27) and also regulates HIF1α expression via mRNA translation (23). MSH2 is a caretaker gene that is responsible for DNA mismatch repair and is involved in many different forms of DNA repair, including transcription-coupled repair (28), homologous recombination (29), and BER (30).…”