Disruption of the RBM38-eIF4E complex with a synthetic peptide PEP8 increases p53 expression

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Rbm38 is a p53 target and an RNA-binding protein known to suppress p53 translation by preventing eukaryotic translation initiation factor 4E (eIF4E) from binding to p53 mRNA. In this study, we show that synthetic peptides corresponding to the binding interface between Rbm38 and eIF4E, including an 8 amino acid peptide (Pep8) derived from Rbm38, are effective in relieving Rbm38-mediated repression of p53. Molecular simulations showed that Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E. Substitution of Ser-6 with Lys, but not with Asp, enhanced the ability of Pep8 to inhibit the Rbm38-eIF4E complex. Importantly, Pep8 alone or together with a low dose of doxorubicin potently induced p53 expression and suppressed colony and tumor sphere formation and xenograft tumors in Rbm38- and p53-dependent manners. Together, we conclude that modulating the Rbm38-eIF4E complex may be explored as a therapeutic strategy for cancers that carry wild-type p53. Significance: Disruption of the Rbm38-eIF4E complex via synthetic peptides induces wild-type p53 expression, suppresses tumor growth and progression, and may serve as a novel cancer therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)807-818
Number of pages12
JournalCancer Research
Volume79
Issue number4
DOIs
StatePublished - Feb 15 2019

Fingerprint

Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Peptides
Neoplasms
RNA-Binding Proteins
Viperidae
Heterografts
Doxorubicin
Hydrogen
Amino Acids
Messenger RNA
Therapeutics
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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.

In: Cancer Research, Vol. 79, No. 4, 15.02.2019, p. 807-818.

Research output: Contribution to journalArticle

Lucchesi, Christopher A. ; Zhang, Jin ; Ma, Buyong ; Chen, Mingyi ; Chen, Xinbin. / Disruption of the RBM38-eIF4E complex with a synthetic peptide PEP8 increases p53 expression. In: Cancer Research. 2019 ; Vol. 79, No. 4. pp. 807-818.
@article{6c73bed271024b30ae6b69dc85b0768f,
title = "Disruption of the RBM38-eIF4E complex with a synthetic peptide PEP8 increases p53 expression",
abstract = "Rbm38 is a p53 target and an RNA-binding protein known to suppress p53 translation by preventing eukaryotic translation initiation factor 4E (eIF4E) from binding to p53 mRNA. In this study, we show that synthetic peptides corresponding to the binding interface between Rbm38 and eIF4E, including an 8 amino acid peptide (Pep8) derived from Rbm38, are effective in relieving Rbm38-mediated repression of p53. Molecular simulations showed that Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E. Substitution of Ser-6 with Lys, but not with Asp, enhanced the ability of Pep8 to inhibit the Rbm38-eIF4E complex. Importantly, Pep8 alone or together with a low dose of doxorubicin potently induced p53 expression and suppressed colony and tumor sphere formation and xenograft tumors in Rbm38- and p53-dependent manners. Together, we conclude that modulating the Rbm38-eIF4E complex may be explored as a therapeutic strategy for cancers that carry wild-type p53. Significance: Disruption of the Rbm38-eIF4E complex via synthetic peptides induces wild-type p53 expression, suppresses tumor growth and progression, and may serve as a novel cancer therapeutic strategy.",
author = "Lucchesi, {Christopher A.} and Jin Zhang and Buyong Ma and Mingyi Chen and Xinbin Chen",
year = "2019",
month = "2",
day = "15",
doi = "10.1158/0008-5472.CAN-18-2209",
language = "English (US)",
volume = "79",
pages = "807--818",
journal = "Cancer Research",
issn = "0008-5472",
number = "4",

}

TY - JOUR

T1 - Disruption of the RBM38-eIF4E complex with a synthetic peptide PEP8 increases p53 expression

AU - Lucchesi, Christopher A.

AU - Zhang, Jin

AU - Ma, Buyong

AU - Chen, Mingyi

AU - Chen, Xinbin

PY - 2019/2/15

Y1 - 2019/2/15

N2 - Rbm38 is a p53 target and an RNA-binding protein known to suppress p53 translation by preventing eukaryotic translation initiation factor 4E (eIF4E) from binding to p53 mRNA. In this study, we show that synthetic peptides corresponding to the binding interface between Rbm38 and eIF4E, including an 8 amino acid peptide (Pep8) derived from Rbm38, are effective in relieving Rbm38-mediated repression of p53. Molecular simulations showed that Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E. Substitution of Ser-6 with Lys, but not with Asp, enhanced the ability of Pep8 to inhibit the Rbm38-eIF4E complex. Importantly, Pep8 alone or together with a low dose of doxorubicin potently induced p53 expression and suppressed colony and tumor sphere formation and xenograft tumors in Rbm38- and p53-dependent manners. Together, we conclude that modulating the Rbm38-eIF4E complex may be explored as a therapeutic strategy for cancers that carry wild-type p53. Significance: Disruption of the Rbm38-eIF4E complex via synthetic peptides induces wild-type p53 expression, suppresses tumor growth and progression, and may serve as a novel cancer therapeutic strategy.

AB - Rbm38 is a p53 target and an RNA-binding protein known to suppress p53 translation by preventing eukaryotic translation initiation factor 4E (eIF4E) from binding to p53 mRNA. In this study, we show that synthetic peptides corresponding to the binding interface between Rbm38 and eIF4E, including an 8 amino acid peptide (Pep8) derived from Rbm38, are effective in relieving Rbm38-mediated repression of p53. Molecular simulations showed that Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E. Substitution of Ser-6 with Lys, but not with Asp, enhanced the ability of Pep8 to inhibit the Rbm38-eIF4E complex. Importantly, Pep8 alone or together with a low dose of doxorubicin potently induced p53 expression and suppressed colony and tumor sphere formation and xenograft tumors in Rbm38- and p53-dependent manners. Together, we conclude that modulating the Rbm38-eIF4E complex may be explored as a therapeutic strategy for cancers that carry wild-type p53. Significance: Disruption of the Rbm38-eIF4E complex via synthetic peptides induces wild-type p53 expression, suppresses tumor growth and progression, and may serve as a novel cancer therapeutic strategy.

UR - http://www.scopus.com/inward/record.url?scp=85061616238&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061616238&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-18-2209

DO - 10.1158/0008-5472.CAN-18-2209

M3 - Article

VL - 79

SP - 807

EP - 818

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 4

ER -