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  • hnRNP E functions in a number of mRNA regulatory


    hnRNP E1 functions in a number of mRNA regulatory processes including transcription [74], [75], splicing [7], [74], [76], [77] and translation [6], [8], [69], [78], interacting with RNAs through CU rich regions such as the differentiation control element (DICE) and the TGFβ activated translation (BAT) element [5], [67]. Several studies have shown that activity of this protein is regulated through phosphorylation at a number of sites including S43, T60 and T127. Our laboratory has shown that the interaction of hnRNP E1 with elongation factor 1α1 in epithelial AS-605240 australia represses the translation of a cohort of mesenchymal-associated transcripts containing a 3′-UTR CU-rich element [5]. TGFβ activates Akt2 which phosphorylates hnRNP E1 on serine 43 leading to the release of this RNA binding protein from translationally silenced transcripts. In addition, p21-activated kinase 1 (PAK1) mediated phosphorylation at T60 and T127 has been shown to induce hnRNP E1 nuclear localization which is thought to be a major regulator of function leading to a switch from translational control to transcriptional and splicing regulation [7], [74]. This mechanism of hnRNP E1 regulation is activated during hypoxia as well, which induces an increase in Akt phosphorylation and nuclear localization of hnRNP E1 leading to decreased eNOS mRNA stability [68]. An overview of the post-transcriptional mechanisms through which hnRNP E1 regulates target transcripts involved in EMT and cancer progression will be discussed in the three sections below; control of alternative splicing, alternative polyadenylation, and translational regulation.
    Concluding remarks Currently, several TGFβ signaling inhibitors are under investigation for the treatment of advanced cancer, including the monoclonal antibody Fresolimumab and the TGFβ receptor kinase inhibitor Galunisertib [122], [123], [124]. In combination with such approaches, blockade of hnRNP E1′s metastasis-promoting functions through the inhibition of Akt and Pak1 signaling may be an effective strategy to attenuate cancer progression. The link between this RNA binding protein and the cancer stem cell phenotype may also be targeted in this approach to control the tumor initiating ability of cells that is linked to recurrence and chemo-resistance. Additional characterization of hnRNP E1 function and regulation in metastatic cancer, as well as the function of this EMT regulator in the stromal compartment of tumors is merited.
    Disclosure of potential conflicts of interest.
    Acknowledgments This work was supported by Grants CA055536 and CA154663 from the National Cancer Institute to PHH. We would like to thank members of the Howe lab for providing helpful feedback during the preparation of this manuscript, in particular Dr. Simon Grelet and Dr. Annamarie Dalton.
    Introduction The ubiquitin-proteasome system is a eukaryotic mechanism of intracellular protein degradation, which regulates basic cellular processes such as cell cycle, division, differentiation, and death [[1], [2], [3]]. Therefore, aberrations of this system are closely related to the pathogenesis of human diseases. Ubiquitination is catalysed by the sequential action of a single ubiquitin-activating enzyme E1 (UBE1) and multiple ubiquitin-conjugating E2 (UBE2) and ubiquitin-protein ligase E3 (UBE3) enzymes, and ubiquitinated proteins are finally degraded by proteasomes [3]. Since UBE1 is the common gatekeeping enzyme for ubiquitination, inhibition of UBE1 enzymatic activity blocks the ubiquitin-proteasome system. Target proteins are degraded by the 26S proteasome after ligation with lysine 48 (K48)-linked ubiquitin chains [3]. Otherwise, K63-linked ubiquitin chains contribute to the cytokine-induced activation of nuclear factor-κB (NF-κB) [4]. The 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (hereafter PYR-41) and related pyrazones are cell-permeable UBE1 inhibitors identified in high-throughput screening of the UBE1–UBE2–UBE3 cascade, which selectively and irreversibly inhibits UBE1 activity [3]. PYR-41 and other related pyrazones enter cells and decrease UBE1-ubiquitin thiolester formation via covalent modification, resulting in irreversible inhibition of the enzymatic activity of UBE1 [[5], [6]]. Since PYR-41 exposure inhibits NF-κB activation and increases the expression level and activity of p53, an anti-tumour protein, it is considered a potent drug for selectively killing transformed cells [5].