Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death

Marie Joëlle Miron, Imed Gallouzi, Josée N. Lavoie, Philip E. Branton

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The adenovirus E4orf4 protein induces p53-independent death of human cancer cells by a mechanism requiring interactions with the Bα subunit of protein phosphatase 2A. When expressed alone E4orf4 localizes predominantly in the nucleus, although significant levels are also present in the cytoplasm. While tyrosine phosphorylation of E4orf4 and recruitment of Src have been linked with E4orf4 cytoplasmic cell death functions, little is known about the functions of E4orf4 in the nucleus. In this study, we identified an arginine-rich motif (E4ARM; residues 66-75) that is necessary and sufficient for nuclear and nucleolar localization. This motif, which is highly homologous to the arginine-rich nuclear and nucleolar localization motif of some lentiviral proteins, was shown to target heterologous proteins to the nucleus and to nucleoli, functions found to be dependent on the overall charge of the motif rather than on specific residues. Furthermore, mutation of arginine residues to alanines but not to lysines in E4ARM was shown to block such targeting activity and, when introduced into full-length E4orf4, to decrease induction of cell death. Finally, coexpression of the ARM motifs of E4orf4, HIV-1 Tat or Rev along with full-length E4orf4 was seen to decrease E4orf4-dependent cell killing. Thus it appears that targeting of E4orf4 to the nucleus and cell nucleoli by E4ARM is an important component of E4orf4-induced cell death.

Original languageEnglish
Pages (from-to)7458-7468
Number of pages11
JournalOncogene
Volume23
Issue number45
DOIs
Publication statusPublished - 30 Sep 2004
Externally publishedYes

Fingerprint

Arginine
Cell Death
Cell Nucleolus
Protein Phosphatase 2
Alanine
Lysine
Tyrosine
HIV-1
Cytoplasm
Proteins
Phosphorylation
Mutation
adenovirus E4orf4 protein
Neoplasms

Keywords

  • Adenovirus
  • Arginine-rich motif
  • Cell death
  • E4orf4
  • Nuclear localization signal
  • Nucleolus
  • Nucleus

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death. / Miron, Marie Joëlle; Gallouzi, Imed; Lavoie, Josée N.; Branton, Philip E.

In: Oncogene, Vol. 23, No. 45, 30.09.2004, p. 7458-7468.

Research output: Contribution to journalArticle

Miron, Marie Joëlle ; Gallouzi, Imed ; Lavoie, Josée N. ; Branton, Philip E. / Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death. In: Oncogene. 2004 ; Vol. 23, No. 45. pp. 7458-7468.
@article{fbc67d715c45428681ec2cb02c7b0a3f,
title = "Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death",
abstract = "The adenovirus E4orf4 protein induces p53-independent death of human cancer cells by a mechanism requiring interactions with the Bα subunit of protein phosphatase 2A. When expressed alone E4orf4 localizes predominantly in the nucleus, although significant levels are also present in the cytoplasm. While tyrosine phosphorylation of E4orf4 and recruitment of Src have been linked with E4orf4 cytoplasmic cell death functions, little is known about the functions of E4orf4 in the nucleus. In this study, we identified an arginine-rich motif (E4ARM; residues 66-75) that is necessary and sufficient for nuclear and nucleolar localization. This motif, which is highly homologous to the arginine-rich nuclear and nucleolar localization motif of some lentiviral proteins, was shown to target heterologous proteins to the nucleus and to nucleoli, functions found to be dependent on the overall charge of the motif rather than on specific residues. Furthermore, mutation of arginine residues to alanines but not to lysines in E4ARM was shown to block such targeting activity and, when introduced into full-length E4orf4, to decrease induction of cell death. Finally, coexpression of the ARM motifs of E4orf4, HIV-1 Tat or Rev along with full-length E4orf4 was seen to decrease E4orf4-dependent cell killing. Thus it appears that targeting of E4orf4 to the nucleus and cell nucleoli by E4ARM is an important component of E4orf4-induced cell death.",
keywords = "Adenovirus, Arginine-rich motif, Cell death, E4orf4, Nuclear localization signal, Nucleolus, Nucleus",
author = "Miron, {Marie Jo{\"e}lle} and Imed Gallouzi and Lavoie, {Jos{\'e}e N.} and Branton, {Philip E.}",
year = "2004",
month = "9",
day = "30",
doi = "10.1038/sj.onc.1207919",
language = "English",
volume = "23",
pages = "7458--7468",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "45",

}

TY - JOUR

T1 - Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death

AU - Miron, Marie Joëlle

AU - Gallouzi, Imed

AU - Lavoie, Josée N.

AU - Branton, Philip E.

PY - 2004/9/30

Y1 - 2004/9/30

N2 - The adenovirus E4orf4 protein induces p53-independent death of human cancer cells by a mechanism requiring interactions with the Bα subunit of protein phosphatase 2A. When expressed alone E4orf4 localizes predominantly in the nucleus, although significant levels are also present in the cytoplasm. While tyrosine phosphorylation of E4orf4 and recruitment of Src have been linked with E4orf4 cytoplasmic cell death functions, little is known about the functions of E4orf4 in the nucleus. In this study, we identified an arginine-rich motif (E4ARM; residues 66-75) that is necessary and sufficient for nuclear and nucleolar localization. This motif, which is highly homologous to the arginine-rich nuclear and nucleolar localization motif of some lentiviral proteins, was shown to target heterologous proteins to the nucleus and to nucleoli, functions found to be dependent on the overall charge of the motif rather than on specific residues. Furthermore, mutation of arginine residues to alanines but not to lysines in E4ARM was shown to block such targeting activity and, when introduced into full-length E4orf4, to decrease induction of cell death. Finally, coexpression of the ARM motifs of E4orf4, HIV-1 Tat or Rev along with full-length E4orf4 was seen to decrease E4orf4-dependent cell killing. Thus it appears that targeting of E4orf4 to the nucleus and cell nucleoli by E4ARM is an important component of E4orf4-induced cell death.

AB - The adenovirus E4orf4 protein induces p53-independent death of human cancer cells by a mechanism requiring interactions with the Bα subunit of protein phosphatase 2A. When expressed alone E4orf4 localizes predominantly in the nucleus, although significant levels are also present in the cytoplasm. While tyrosine phosphorylation of E4orf4 and recruitment of Src have been linked with E4orf4 cytoplasmic cell death functions, little is known about the functions of E4orf4 in the nucleus. In this study, we identified an arginine-rich motif (E4ARM; residues 66-75) that is necessary and sufficient for nuclear and nucleolar localization. This motif, which is highly homologous to the arginine-rich nuclear and nucleolar localization motif of some lentiviral proteins, was shown to target heterologous proteins to the nucleus and to nucleoli, functions found to be dependent on the overall charge of the motif rather than on specific residues. Furthermore, mutation of arginine residues to alanines but not to lysines in E4ARM was shown to block such targeting activity and, when introduced into full-length E4orf4, to decrease induction of cell death. Finally, coexpression of the ARM motifs of E4orf4, HIV-1 Tat or Rev along with full-length E4orf4 was seen to decrease E4orf4-dependent cell killing. Thus it appears that targeting of E4orf4 to the nucleus and cell nucleoli by E4ARM is an important component of E4orf4-induced cell death.

KW - Adenovirus

KW - Arginine-rich motif

KW - Cell death

KW - E4orf4

KW - Nuclear localization signal

KW - Nucleolus

KW - Nucleus

UR - http://www.scopus.com/inward/record.url?scp=6344248656&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=6344248656&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1207919

DO - 10.1038/sj.onc.1207919

M3 - Article

C2 - 15334069

AN - SCOPUS:6344248656

VL - 23

SP - 7458

EP - 7468

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 45

ER -