Unknown

Dataset Information

0

CHK1 regulates NF-?B 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-?B and induction of NF-?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-?B activity. Our data provide evidence that targeting CHK1 in p53-deficient cancers may abrogate NF-?B signaling that is associated with increased cellular survival and chemoresistance.

SUBMITTER: Carroll BL 

PROVIDER: S-EPMC4951279 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

CHK1 regulates NF-κB signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles.

Carroll Brittany L BL   Pulkoski-Gross Michael J MJ   Hannun Yusuf A YA   Obeid Lina M LM  

Oncotarget 20160401 14


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  ...[more]

Similar Datasets

| S-EPMC1280285 | biostudies-literature
| S-EPMC2656159 | biostudies-literature
| S-EPMC3314455 | biostudies-literature
| S-EPMC9815235 | biostudies-literature
| S-EPMC7268994 | biostudies-literature
| S-EPMC6999715 | biostudies-literature
| S-EPMC2131784 | biostudies-literature
| S-EPMC3381958 | biostudies-literature
| S-EPMC3150487 | biostudies-literature
| S-EPMC5342109 | biostudies-literature