title: CHK1 regulates NF-κB signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles.
abstract: The recently discovered CHK1-Suppressed (CS) pathway is activated by inhibition or loss of the checkpoint kinase CHK1, promoting an apoptotic response to DNA damage mediated by caspase-2 in p53-deficient cells. Although functions of the CS-pathway have been investigated biochemically, it remains unclear whether and how CHK1 inhibition can be regulated endogenously and whether this constitutes a key component of the DNA damage response (DDR). Here, we present data that define the first endogenous activation of the CS-pathway whereby, upon DNA damage, wild type p53 acts as an endogenous regulator of CHK1 levels that modulates caspase-2 activation. Moreover, we demonstrate that persistence of CHK1 levels in response to DNA damage in p53-deficient cancer cells, leads to CHK1-mediated activation of NF-κB and induction of NF-κB-regulated genes in cells and in associated tumor-derived microvesicles (TMVs), both of which are abrogated by loss or inhibition of CHK1. These data define a novel role for CHK1 in the DDR pathway as a regulator NF-κB activity. Our data provide evidence that targeting CHK1 in p53-deficient cancers may abrogate NF-κB signaling that is associated with increased cellular survival and chemoresistance.
authors.affiliation: Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Carroll
authors.affiliation: Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA.|Pharmacological Sciences, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pulkoski-Gross
authors.affiliation: Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA.|Northport Veterans Affairs Medical Center, Northport, New York, USA.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
mesh_terms: D000818:Animals; D053143:Caspase 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D045325:HCT116 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D061986:MCF-7 Cells; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000072000:NF-KappaB Inhibitor alpha; D004317:Doxorubicin; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases
keywords: CHK1; DNA damage; p53; tumor microvesicles