Regulation of XIAP Translation and Induction by MDM2 following Irradiation

Lubing Gu; Ningxi Zhu; Hongying Zhang; Donald L. Durden; Yue Feng; Muxiang Zhou

doi:10.1016/j.ccr.2009.03.002

Regulation of XIAP Translation and Induction by MDM2 following Irradiation

Lubing Gu, Ningxi Zhu, Hongying Zhang, Donald L. Durden, Yue Feng, Muxiang Zhou

Research output: Contribution to journal › Article › peer-review

152 Scopus citations

Abstract

Increases in protein levels of XIAP in cancer cells have been associated with resistance to apoptosis induced by cellular stress. Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 at the translational level. MDM2 was found to physically interact with the IRES of the XIAP 5′-UTR, and to positively regulate XIAP IRES activity. This XIAP IRES-dependent translation was significantly increased in MDM2-transfected cells where MDM2 accumulated in the cytoplasm. Cellular stress and DNA damage triggered by irradiation induced the dephosphorylation and cytoplasmic localization of MDM2, which also led to an increase in IRES-dependent XIAP translation. Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis.

Original language	English (US)
Pages (from-to)	363-375
Number of pages	13
Journal	Cancer Cell
Volume	15
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2009.03.002
State	Published - May 5 2009
Externally published	Yes

Keywords

CELLCYCLE

ASJC Scopus subject areas

Oncology
Cancer Research

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@article{edc77ec2e3734aef9402e428984ee611,

title = "Regulation of XIAP Translation and Induction by MDM2 following Irradiation",

abstract = "Increases in protein levels of XIAP in cancer cells have been associated with resistance to apoptosis induced by cellular stress. Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 at the translational level. MDM2 was found to physically interact with the IRES of the XIAP 5′-UTR, and to positively regulate XIAP IRES activity. This XIAP IRES-dependent translation was significantly increased in MDM2-transfected cells where MDM2 accumulated in the cytoplasm. Cellular stress and DNA damage triggered by irradiation induced the dephosphorylation and cytoplasmic localization of MDM2, which also led to an increase in IRES-dependent XIAP translation. Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis.",

keywords = "CELLCYCLE",

author = "Lubing Gu and Ningxi Zhu and Hongying Zhang and Durden, {Donald L.} and Yue Feng and Muxiang Zhou",

note = "Funding Information: We are most grateful to Dr. Martin Holcik and Dr. Richard E. Lloyd for providing us with the bicistronic plasmid pβgal-XIAP-CAT and dicistronic plasmid pRL-XIAP-FL, respectively. This work was supported by grants from the NIH (R01 CA123490), The Leukemia and Lymphoma Society (6033-08), and CURE. ",

year = "2009",

month = may,

day = "5",

doi = "10.1016/j.ccr.2009.03.002",

language = "English (US)",

volume = "15",

pages = "363--375",

journal = "Cancer Cell",

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T1 - Regulation of XIAP Translation and Induction by MDM2 following Irradiation

AU - Gu, Lubing

AU - Zhu, Ningxi

AU - Zhang, Hongying

AU - Durden, Donald L.

AU - Feng, Yue

AU - Zhou, Muxiang

N1 - Funding Information: We are most grateful to Dr. Martin Holcik and Dr. Richard E. Lloyd for providing us with the bicistronic plasmid pβgal-XIAP-CAT and dicistronic plasmid pRL-XIAP-FL, respectively. This work was supported by grants from the NIH (R01 CA123490), The Leukemia and Lymphoma Society (6033-08), and CURE.

PY - 2009/5/5

Y1 - 2009/5/5

N2 - Increases in protein levels of XIAP in cancer cells have been associated with resistance to apoptosis induced by cellular stress. Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 at the translational level. MDM2 was found to physically interact with the IRES of the XIAP 5′-UTR, and to positively regulate XIAP IRES activity. This XIAP IRES-dependent translation was significantly increased in MDM2-transfected cells where MDM2 accumulated in the cytoplasm. Cellular stress and DNA damage triggered by irradiation induced the dephosphorylation and cytoplasmic localization of MDM2, which also led to an increase in IRES-dependent XIAP translation. Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis.

AB - Increases in protein levels of XIAP in cancer cells have been associated with resistance to apoptosis induced by cellular stress. Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 at the translational level. MDM2 was found to physically interact with the IRES of the XIAP 5′-UTR, and to positively regulate XIAP IRES activity. This XIAP IRES-dependent translation was significantly increased in MDM2-transfected cells where MDM2 accumulated in the cytoplasm. Cellular stress and DNA damage triggered by irradiation induced the dephosphorylation and cytoplasmic localization of MDM2, which also led to an increase in IRES-dependent XIAP translation. Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis.

KW - CELLCYCLE

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SN - 1535-6108

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EP - 375

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Regulation of XIAP Translation and Induction by MDM2 following Irradiation

Abstract

Keywords

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