Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest

Weidong Yong, Shideng Bao, Hanying Chen, Dapei Li, Edwin R. Sánchez, Weinian Shou

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Protein phosphatase 5 (Ppp5), a tetratricopeptide repeat domain protein, has been implicated in multiple cellular functions, including cellular proliferation, migration, differentiation and survival, and cell cycle checkpoint regulation via the ataxia telangiectasia mutated/ATM and Rad3-related (ATM/ATR) signal pathway. However, the physiological functions of Ppp5 have not been reported. To confirm the role of Ppp5 in cell cycle checkpoint regulation, we generated Ppp5-deficient mice and isolated mouse embryonic fibroblast (MEF) cells from Ppp5-deficient and littermate control embryos. Although Ppp5-deficient mice can survive through embryonic development and postnatal life and MEF cells from the Ppp5-deficient mice maintain normal replication checkpoint induced by hydroxyurea, Ppp5-deficient MEF cells display a significant defect in G2/M DNA damage checkpoint in response to ionizing radiation (IR). To determine whether this defect in IR-induced G 2/M checkpoint is due to altered ATM-mediated signaling, we measured ATM kinase activity and ATM-mediated downstream events. Our data demonstrated that IR-induced ATM kinase activity is attenuated in Ppp5-deficient MEFs. Phosphorylation levels of two known ATM substrates, Rad17 and Chk2, were significantly reduced in Ppp5-deficient MEFs in response to IR. Furthermore, DNA damage-induced Rad17 nuclear foci were dramatically reduced in Ppp5-deficient MEFs. These results demonstrate a direct regulatory linkage between Ppp5 and activation of the ATM-mediated G2/M DNA damage checkpoint pathway in vivo.

Original languageEnglish
Pages (from-to)14690-14694
Number of pages5
JournalJournal of Biological Chemistry
Volume282
Issue number20
DOIs
StatePublished - May 18 2007

Fingerprint

Ataxia Telangiectasia
Cell Cycle Checkpoints
Cells
Ionizing radiation
Ionizing Radiation
Fibroblasts
DNA Damage
protein phosphatase 5
DNA
Phosphotransferases
Defects
Phosphorylation
Hydroxyurea
Embryonic Development
Signal Transduction
Embryonic Structures

ASJC Scopus subject areas

  • Biochemistry

Cite this

Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest. / Yong, Weidong; Bao, Shideng; Chen, Hanying; Li, Dapei; Sánchez, Edwin R.; Shou, Weinian.

In: Journal of Biological Chemistry, Vol. 282, No. 20, 18.05.2007, p. 14690-14694.

Research output: Contribution to journalArticle

@article{bed7caf62b7746b8a7eb0251db8ba0b6,
title = "Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest",
abstract = "Protein phosphatase 5 (Ppp5), a tetratricopeptide repeat domain protein, has been implicated in multiple cellular functions, including cellular proliferation, migration, differentiation and survival, and cell cycle checkpoint regulation via the ataxia telangiectasia mutated/ATM and Rad3-related (ATM/ATR) signal pathway. However, the physiological functions of Ppp5 have not been reported. To confirm the role of Ppp5 in cell cycle checkpoint regulation, we generated Ppp5-deficient mice and isolated mouse embryonic fibroblast (MEF) cells from Ppp5-deficient and littermate control embryos. Although Ppp5-deficient mice can survive through embryonic development and postnatal life and MEF cells from the Ppp5-deficient mice maintain normal replication checkpoint induced by hydroxyurea, Ppp5-deficient MEF cells display a significant defect in G2/M DNA damage checkpoint in response to ionizing radiation (IR). To determine whether this defect in IR-induced G 2/M checkpoint is due to altered ATM-mediated signaling, we measured ATM kinase activity and ATM-mediated downstream events. Our data demonstrated that IR-induced ATM kinase activity is attenuated in Ppp5-deficient MEFs. Phosphorylation levels of two known ATM substrates, Rad17 and Chk2, were significantly reduced in Ppp5-deficient MEFs in response to IR. Furthermore, DNA damage-induced Rad17 nuclear foci were dramatically reduced in Ppp5-deficient MEFs. These results demonstrate a direct regulatory linkage between Ppp5 and activation of the ATM-mediated G2/M DNA damage checkpoint pathway in vivo.",
author = "Weidong Yong and Shideng Bao and Hanying Chen and Dapei Li and S{\'a}nchez, {Edwin R.} and Weinian Shou",
year = "2007",
month = "5",
day = "18",
doi = "10.1074/jbc.C700019200",
language = "English",
volume = "282",
pages = "14690--14694",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "20",

}

TY - JOUR

T1 - Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest

AU - Yong, Weidong

AU - Bao, Shideng

AU - Chen, Hanying

AU - Li, Dapei

AU - Sánchez, Edwin R.

AU - Shou, Weinian

PY - 2007/5/18

Y1 - 2007/5/18

N2 - Protein phosphatase 5 (Ppp5), a tetratricopeptide repeat domain protein, has been implicated in multiple cellular functions, including cellular proliferation, migration, differentiation and survival, and cell cycle checkpoint regulation via the ataxia telangiectasia mutated/ATM and Rad3-related (ATM/ATR) signal pathway. However, the physiological functions of Ppp5 have not been reported. To confirm the role of Ppp5 in cell cycle checkpoint regulation, we generated Ppp5-deficient mice and isolated mouse embryonic fibroblast (MEF) cells from Ppp5-deficient and littermate control embryos. Although Ppp5-deficient mice can survive through embryonic development and postnatal life and MEF cells from the Ppp5-deficient mice maintain normal replication checkpoint induced by hydroxyurea, Ppp5-deficient MEF cells display a significant defect in G2/M DNA damage checkpoint in response to ionizing radiation (IR). To determine whether this defect in IR-induced G 2/M checkpoint is due to altered ATM-mediated signaling, we measured ATM kinase activity and ATM-mediated downstream events. Our data demonstrated that IR-induced ATM kinase activity is attenuated in Ppp5-deficient MEFs. Phosphorylation levels of two known ATM substrates, Rad17 and Chk2, were significantly reduced in Ppp5-deficient MEFs in response to IR. Furthermore, DNA damage-induced Rad17 nuclear foci were dramatically reduced in Ppp5-deficient MEFs. These results demonstrate a direct regulatory linkage between Ppp5 and activation of the ATM-mediated G2/M DNA damage checkpoint pathway in vivo.

AB - Protein phosphatase 5 (Ppp5), a tetratricopeptide repeat domain protein, has been implicated in multiple cellular functions, including cellular proliferation, migration, differentiation and survival, and cell cycle checkpoint regulation via the ataxia telangiectasia mutated/ATM and Rad3-related (ATM/ATR) signal pathway. However, the physiological functions of Ppp5 have not been reported. To confirm the role of Ppp5 in cell cycle checkpoint regulation, we generated Ppp5-deficient mice and isolated mouse embryonic fibroblast (MEF) cells from Ppp5-deficient and littermate control embryos. Although Ppp5-deficient mice can survive through embryonic development and postnatal life and MEF cells from the Ppp5-deficient mice maintain normal replication checkpoint induced by hydroxyurea, Ppp5-deficient MEF cells display a significant defect in G2/M DNA damage checkpoint in response to ionizing radiation (IR). To determine whether this defect in IR-induced G 2/M checkpoint is due to altered ATM-mediated signaling, we measured ATM kinase activity and ATM-mediated downstream events. Our data demonstrated that IR-induced ATM kinase activity is attenuated in Ppp5-deficient MEFs. Phosphorylation levels of two known ATM substrates, Rad17 and Chk2, were significantly reduced in Ppp5-deficient MEFs in response to IR. Furthermore, DNA damage-induced Rad17 nuclear foci were dramatically reduced in Ppp5-deficient MEFs. These results demonstrate a direct regulatory linkage between Ppp5 and activation of the ATM-mediated G2/M DNA damage checkpoint pathway in vivo.

UR - http://www.scopus.com/inward/record.url?scp=34447525646&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447525646&partnerID=8YFLogxK

U2 - 10.1074/jbc.C700019200

DO - 10.1074/jbc.C700019200

M3 - Article

C2 - 17376776

AN - SCOPUS:34447525646

VL - 282

SP - 14690

EP - 14694

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 20

ER -