Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53.
 ...
PMID:Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. 1856 May 58

Fusogenic HIV-1 isolates induce the fusion of infected and bystander cells. Such syncytia can be found as "multinucleated giant cells" in the brain from HIV-1-infected individuals, as well as in lymphoid tissues. Syncytia elicited by the HIV-1 envelope glycoprotein (Env) manifest the aggregation of PML in discrete nuclear bodies and the recruitment of TopBP1, NBS1 and ATM to DNA damage foci containing phosphorylated ATM and histone H2AX ("-H2AX). This DNA damage response then culminates in p53-dependent activation of the mitochondrial pathway of apoptosis. Here, we show that Env-elicited syncytia also manifest activating phosphorylations of the checkpoint kinases 1 and 2 (Chk1 and Chk2), and both Chk1 and Chk2 colocalize with "-H2AX foci. However, only the siRNA-mediated knockdown of Chk2, not the depletion of Chk1, inhibits mitochondrial outer membrane permeabilization and subsequent syncytial apoptosis. Depletion of PML, TopBP1, NBS1 or ATM inhibit the activating phosphorylation of Chk2. Altogether, these results indicate that Chk2 (but not Chk1) participates in the DNA damage-elicited pro-apoptotic cascade that leads to the demise of Env-elicited syncytia.
 ...
PMID:Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope. 1916 52