In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma

被引：266

作者：

Mir, Shahryar E. ^{[1
,2
]}

Hamer, Philip C. De Witt ^{[1
,2
]}

Krawczyk, Przemek M. ^{[3
]}

Balaj, Leonora ^{[1
,2
]}

Claes, An ^{[6
]}

Niers, Johanna M. ^{[1
,2
,7
,8
]}

Van Tilborg, Angela A. G. ^{[3
]}

Zwinderman, Aeilko H. ^{[5
]}

Geerts, Dirk ^{[4
]}

Kaspers, Gertjan J. L. ^{[1
,2
]}

Vandertop, W. Peter ^{[1
,2
]}

Cloos, Jacqueline ^{[1
,2
]}

Tannous, Bakhos A. ^{[7
,8
]}

Wesseling, Pieter ^{[6
]}

Aten, Jacob A. ^{[3
]}

Noske, David P. ^{[1
,2
]}

Van Noorden, Cornelis J. F. ^{[3
]}

Wurdinger, Thomas ^{[1
,2
,7
,8
]}

机构：

[1] Vrije Univ Amsterdam Med Ctr, Neurooncol Res Grp, Dept Neurosurg, NL-1081 HV Amsterdam, Netherlands

[2] Vrije Univ Amsterdam Med Ctr, Neurooncol Res Grp, Dept Pediat Oncol Hematol, NL-1081 HV Amsterdam, Netherlands

[3] Univ Amsterdam, Acad Med Ctr, Dept Cell Biol & Histol, NL-1100 DD Amsterdam, Netherlands

[4] Univ Amsterdam, Acad Med Ctr, Dept Human Genet, NL-1100 DD Amsterdam, Netherlands

[5] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol & Biostat, NL-1100 DD Amsterdam, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 GA Nijmegen, Netherlands

[7] Massachusetts Gen Hosp, Dept Neurol, Mol Neurogenet Unit, Charlestown, MA 02113 USA

[8] Harvard Univ, Sch Med, Charlestown, MA 02113 USA

来源：

CANCER CELL | 2010年 / 18卷 / 03期

关键词：

DNA-DAMAGE CHECKPOINT; TUMOR STEM-CELLS; RANDOMIZED PHASE-III; DOUBLE-STRAND BREAKS; PROTEIN-KINASE; MALIGNANT GLIOMAS; GENE-EXPRESSION; G(2) CHECKPOINT; LUNG-CANCER; COPY NUMBER;

D O I：

10.1016/j.ccr.2010.08.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Kinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G(2) checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G(2) arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma.

引用

页码：244 / 257

页数：14

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