alexa Death receptor-induced activation of the Chk2- and histone H2AX-associated DNA damage response pathways.
Microbiology

Microbiology

Journal of Antivirals & Antiretrovirals

Author(s): Solier S, Sordet O, Kohn KW, Pommier Y

Abstract Share this page

Abstract TRAIL is an endogenous death receptor ligand also used therapeutically because of its selective proapoptotic activity in cancer cells. In the present study, we examined chromatin alterations induced by TRAIL and show that TRAIL induces a rapid activation of DNA damage response (DDR) pathways with histone H2AX, Chk2, ATM, and DNA-PK phosphorylations. Within 1 h of TRAIL exposure, immunofluorescence confocal microscopy revealed gamma-H2AX peripheral nuclear staining (gamma-H2AX ring) colocalizing with phosphorylated/activated Chk2, ATM, and DNA-PK inside heterochromatin regions. The marginal distribution of DDR proteins in early apoptotic cells is remarkably different from the focal staining seen after DNA damage. TRAIL-induced DDR was suppressed upon caspase inhibition or Bax inactivation, demonstrating that the DDR activated by TRAIL is downstream from the mitochondrial death pathway. H2AX phosphorylation was dependent on DNA-PK, while Chk2 phosphorylation was dependent on both ATM and DNA-PK. Downregulation of Chk2 decreased TRAIL-induced cell detachment; delayed the activation of caspases 2, 3, 8, and 9; and reduced TRAIL-induced cell killing. Together, our findings suggest that nuclear activation of Chk2 by TRAIL acts as a positive feedback loop involving the mitochondrion-dependent activation of caspases, independently of p53.
This article was published in Mol Cell Biol and referenced in Journal of Antivirals & Antiretrovirals

Relevant Expert PPTs

Relevant Speaker PPTs

  • Aisa N. Muya
    Clinical and immunologic pattern of PLHIV lost from HIV care before initiated Antiretroviral treatment within an HIV Program in Tanzania
    PPT Version | PDF Version
  • Marcus Motshwane
    Modelling the efficacy of antiretroviral treatment in HIV patients: The case of Dr George Mukhari Academic Hospital in Tshwane, Gauteng province of South Africa
    PPT Version | PDF Version

Recommended Conferences

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords