Disruption of the Rbm38-eIF4E Complex with a Synthetic Peptide Pep8 Increases p53 Expression

Lucchesi, Christopher A.; Zhang, Jin; Ma, Buyong; Chen, Mingyi; Chen, Xinbin

doi:10.1158/0008-5472.can-18-2209

Cited by 34 publications

(41 citation statements)

References 48 publications

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“…Synthetic peptides have also been used to interrupt the RBM38-eIF4E interaction, with the goal of suppressing translation of the p53 mRNA. Using this strategy, p53 levels were upregulated and tumor growth was inhibited in vitro and in vivo [ 205 ].…”

Section: Rbps As Therapeutic Targets In Cancermentioning

confidence: 99%

RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives

Kang

Lee

2020

Cancers

101

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RNA-binding proteins (RBPs) crucially regulate gene expression through post-transcriptional regulation, such as by modulating microRNA (miRNA) processing and the alternative splicing, alternative polyadenylation, subcellular localization, stability, and translation of RNAs. More than 1500 RBPs have been identified to date, and many of them are known to be deregulated in cancer. Alterations in the expression and localization of RBPs can influence the expression levels of oncogenes, tumor-suppressor genes, and genome stability-related genes. RBP-mediated gene regulation can lead to diverse cancer-related cellular phenotypes, such as proliferation, apoptosis, angiogenesis, senescence, and epithelial-mesenchymal transition (EMT)/invasion/metastasis. This regulation can also be associated with cancer prognosis. Thus, RBPs can be potential targets for the development of therapeutics for the cancer treatment. In this review, we describe the molecular functions of RBPs, their roles in cancer-related cellular phenotypes, and various approaches that may be used to target RBPs for cancer treatment.

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Section: Rbps As Therapeutic Targets In Cancermentioning

confidence: 99%

RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives

Kang

Lee

2020

Cancers

101

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“…Furthermore, the disclosure of the dual effects of eIF4E2-GSK3β leads to effective cancer suppression strategy by combining peptide e2-I with Pep8. e2-I induced-senescence inhibited NSCLC A549 xenograft tumor growth in p53-dependent manners, while peptide Pep8 greatly boosted this effect by negating the negative effect of RBM38 dephosphorylation on p53 (Lucchesi et al, 2019). Especially, the low concentration of Pep8 is impotent, but when combined with e2-I, it is very effective.…”

Section: Discussionmentioning

confidence: 98%

“…Then, the A549 xenograft model was used to further evaluate the antitumor activity of e2-I by intratumor injection after xenograft tumors reached 100 mm 3 in size. e2-I reduces the growth of xenograft tumors compared to e2-S (Fig EV4H and I), and SA-β-Gal staining showed e2-I promotes senescence (Fig EV4J, left panel), accompanied by a decrease of TOPBP1 expression or an increase of p21 expression in xenograft tumors(Fig EV4J, right panel).RBM38 Ser195 dephosphorylation may restrict the effect of e2-I by inhibiting p53, and a novel peptide Pep8 may relieve this restriction by disrupting RBM38-eIF4E binding(Lucchesi et al, 2019). Pep8, at a relative low concentration of 1μM, negligibly inhibited xenograft growth with no p53 induction.…”

mentioning

confidence: 94%

Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia

Zhang

Sun

et al. 2020

Preprint

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Cellular senescence is a stable state of cell cycle arrest elicited by various stresses. Hypoxia modulates senescence, but its consequences and implications in living organisms remains unknown. Here we identified the eIF4E2-GSK3β pathway regulated by hypoxia to maintain p53 proline-directed phosphorylation (S/T-P) to prevent senescence. We previously knew that GSK3β activates p53 translation through phosphorylation of RBM38 Ser195 (-Pro196). Unexpectedly, eIF4E2 directly binds to GSK3β via a conserved motif, mediating Ser195 phosphorylation. Phosphoproteomics revealed that eIF4E2-GSK3β specifically regulates proline-directed phosphorylation. Peptide e2-I or G3-I that disrupts this pathway dephosphorylates p53 at multiple S/T-P, which accelerate senescence by transcriptional suppressing TOPBP1 and TRX1. Consistently, peptides induce liver senescence that is rescued by TOPBP1 expression, and mediate senescence-dependent tumor regression. Furthermore, hypoxia inhibits eIF4E2-GSK3β. Inspiringly, eIF4E2-GSK3β is unique to mammals, which maintains mice viability and prevents liver senescence against physiological hypoxia. Interestingly, this mammalian eIF4E2 protects heart of zebrafish against hypoxia. Together, we identified a mammalian -unique eIF4E2-GSK3β pathway preventing senescence and guarding against hypoxia in vivo.

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“…Although the sequence outside the RRM is relatively divergent, at least two conserved domains can be identified in the C-terminal half of vertebrate Rbm24 and Rbm38 [ 25 ]. In particular, a motif close to the extreme C-terminus, which contains a serine residue (serine 181 in Rbm24 and serine 195 in Rbm38), interacts with eukaryote initiation factor 4E (eIF4E) and prevents it from binding to the 5’-cap of mRNAs [ 26 , 27 ]. However, at least in several cancer cell lines, phosphorylation of the serine residue by glycogen synthase kinase 3 (GSK3) prevents the interaction with eIF4E and converts Rbm24 or Rbm38 into an activator of mRNA translation [ 28 ].…”

Section: Rbm24 Functional Domainsmentioning

confidence: 99%

RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

Grifone

Shao

Saquet

et al. 2020

Cells

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RNA-binding proteins control the metabolism of RNAs at all stages of their lifetime. They are critically required for the post-transcriptional regulation of gene expression in a wide variety of physiological and pathological processes. Rbm24 is a highly conserved RNA-binding protein that displays strongly regionalized expression patterns and exhibits dynamic changes in subcellular localization during early development. There is increasing evidence that it acts as a multifunctional regulator to switch cell fate determination and to maintain tissue homeostasis. Dysfunction of Rbm24 disrupts cell differentiation in nearly every tissue where it is expressed, such as skeletal and cardiac muscles, and different head sensory organs, but the molecular events that are affected may vary in a tissue-specific, or even a stage-specific manner. Recent works using different animal models have uncovered multiple post-transcriptional regulatory mechanisms by which Rbm24 functions in key developmental processes. In particular, it represents a major splicing factor in muscle cell development, and plays an essential role in cytoplasmic polyadenylation during lens fiber cell terminal differentiation. Here we review the advances in understanding the implication of Rbm24 during development and disease, by focusing on its regulatory roles in physiological and pathological conditions.

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Disruption of the Rbm38-eIF4E Complex with a Synthetic Peptide Pep8 Increases p53 Expression

Cited by 34 publications

References 48 publications

RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives

RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives

Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia

RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

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