Lack of PTEN sequesters CHK1 and initiates genetic instability

Janusz Puc; Megan Keniry; Hong Shen Li; Tej K. Pandita; Atish D. Choudhury; Lorenzo Memeo; Mahesh Mansukhani; Vundavalli V.V.S. Murty; Zbigniew Gaciong; Sarah E.M. Meek; Helen Piwnica-Worms; Hanina Hibshoosh; Ramon Parsons

doi:10.1016/j.ccr.2005.01.009

Lack of PTEN sequesters CHK1 and initiates genetic instability

Janusz Puc, Megan Keniry, Hong Shen Li, Tej K. Pandita, Atish D. Choudhury, Lorenzo Memeo, Mahesh Mansukhani, Vundavalli V.V.S. Murty, Zbigniew Gaciong, Sarah E.M. Meek, Helen Piwnica-Worms, Hanina Hibshoosh, Ramon Parsons

Academic Institute

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

279 Scopus citations

Abstract

Pten^-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p < 0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.

Original language	English (US)
Pages (from-to)	193-204
Number of pages	12
Journal	Cancer Cell
Volume	7
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2005.01.009
State	Published - Feb 2005

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2005.01.009

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title = "Lack of PTEN sequesters CHK1 and initiates genetic instability",

abstract = "Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p < 0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.",

author = "Janusz Puc and Megan Keniry and Li, {Hong Shen} and Pandita, {Tej K.} and Choudhury, {Atish D.} and Lorenzo Memeo and Mahesh Mansukhani and Murty, {Vundavalli V.V.S.} and Zbigniew Gaciong and Meek, {Sarah E.M.} and Helen Piwnica-Worms and Hanina Hibshoosh and Ramon Parsons",

note = "Funding Information: This work was supported by NCI grant R01 CA82783 and the Avon Foundation to R.P. and NS34746, Department of Army, A-T Children{\textquoteright}s Society to T.K.P. J.P. was supported by NCI training grant T32 CA09503. M.K. is supported by DOD grant PC030849. We would like to thank Drs. Richard Baer, Wei Gu, Thomas Franke, Virginia Papaioannou, Stephen Elledge, Angela Ferguson, Morris Birnbaum, and Thomas Ludwig for providing various reagents and advice that aided this study. ",

year = "2005",

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doi = "10.1016/j.ccr.2005.01.009",

language = "English (US)",

volume = "7",

pages = "193--204",

journal = "Cancer Cell",

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T1 - Lack of PTEN sequesters CHK1 and initiates genetic instability

AU - Puc, Janusz

AU - Keniry, Megan

AU - Li, Hong Shen

AU - Pandita, Tej K.

AU - Choudhury, Atish D.

AU - Memeo, Lorenzo

AU - Mansukhani, Mahesh

AU - Murty, Vundavalli V.V.S.

AU - Gaciong, Zbigniew

AU - Meek, Sarah E.M.

AU - Piwnica-Worms, Helen

AU - Hibshoosh, Hanina

AU - Parsons, Ramon

N1 - Funding Information: This work was supported by NCI grant R01 CA82783 and the Avon Foundation to R.P. and NS34746, Department of Army, A-T Children’s Society to T.K.P. J.P. was supported by NCI training grant T32 CA09503. M.K. is supported by DOD grant PC030849. We would like to thank Drs. Richard Baer, Wei Gu, Thomas Franke, Virginia Papaioannou, Stephen Elledge, Angela Ferguson, Morris Birnbaum, and Thomas Ludwig for providing various reagents and advice that aided this study.

PY - 2005/2

Y1 - 2005/2

N2 - Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p < 0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.

AB - Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p < 0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.

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Lack of PTEN sequesters CHK1 and initiates genetic instability

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