title: JNK signaling is needed to tolerate chromosomal instability.
abstract: Chromosomal instability (CIN), as a common feature of tumors, represents a potential therapeutic target if ways can be found to specifically cause apoptosis in unstably dividing cells. We have previously shown that if signaling through the JNK pathway is reduced, apoptosis is triggered in models of chromosomal instability induced by loss of the spindle checkpoint. Here we identify components upstream and downstream of JNK that are able to mediate this effect, and test the involvement of p53 and DNA damage in causing apoptosis when JNK signaling is reduced in CIN cells. We show that cell cycle progression timing has a strong effect on the apoptosis seen when JNK signaling is reduced in genetically unstable cells: a shortened G 2 phase enhances the apoptosis, while lengthening G 2 rescues the JNK-deficient CIN cell death phenotype. Our findings suggest that chromosomal instability represents a significant stress to dividing cells, and that without JNK signaling, cells undergo apoptosis because they lack a timely and effective response to DNA damage.
authors: Department of Genetics; University of Melbourne; Melbourne, VIC, Australia.
authors: Heidi W-S
authors: HW
authors: Wong
authors: School of Molecular and Biomedical Sciences; University of Adelaide; Adelaide, SA, Australia.
authors: Zeeshan
authors: Z
authors: Shaukat
authors: Department of Genetics; University of Melbourne; Melbourne, VIC, Australia.
authors: Jianbin
authors: J
authors: Wang
authors: Department of Genetics; University of Melbourne; Melbourne, VIC, Australia; School of Molecular and Biomedical Sciences; University of Adelaide; Adelaide, SA, Australia.
authors: Robert
authors: R
authors: Saint
authors: School of Molecular and Biomedical Sciences; University of Adelaide; Adelaide, SA, Australia.
authors: Stephen L
authors: SL
authors: Gregory
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D043171:Chromosomal Instability / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D016195:G2 Phase / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008938:Mitosis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D016159:Tumor Suppressor Protein p53; C474203:p53 protein, Drosophila; D048670:MAP Kinase Kinase 4; D020169:Caspases
keywords: Drosophila; JNK; Mad2; apoptosis; chromosomal instability