CHK1 regulates NF-κB signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles
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Brittany L. Carroll1, Michael J. Pulkoski-Gross1,2, Yusuf A. Hannun1, Lina M. Obeid1,3
1Stony Brook Cancer Center and The Department of Medicine, Stony Brook, New York, USA
2Pharmacological Sciences, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA
3Northport Veterans Affairs Medical Center, Northport, New York, USA
Lina M. Obeid, email: firstname.lastname@example.org
Keywords: p53, CHK1, DNA damage, tumor microvesicles
Received: October 07, 2015 Accepted: January 23, 2016 Published: February 22, 2016
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.
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