Journal
ONCOTARGET
Volume 7, Issue 14, Pages 18159-18170Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7566
Keywords
p53; CHK1; DNA damage; tumor microvesicles
Categories
Funding
- Veterans Affairs Merit Award
- NIH [GM062887, GM097741, P01CA097132, NIH F31 CA186547-01]
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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 kappa B and induction of NF-kappa B-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 kappa B activity. Our data provide evidence that targeting CHK1 in p53-deficient cancers may abrogate NF-kappa B signaling that is associated with increased cellular survival and chemoresistance.
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