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)

Mechanisms underlying histone deacetylase inhibitor (HDACI)-mediated NF-kappaB activation were investigated in human leukemia cells. Exposure of U937 and other leukemia cells to LBH-589 induced reactive oxygen species (ROS) followed by single strand (XRCC1) and double strand (gamma-H2AX) DNA breaks. Notably, LBH-589 lethality was markedly attenuated by small interfering RNA (siRNA) knockdown of the DNA damage-linked histone, H1.2. LBH-589 triggered p65/RelA activation, NF-kappaB-dependent induction of Mn-SOD2, and ROS elimination. Interference with LBH-589-mediated NF-kappaB activation (e.g. in I kappaB alpha super-repressor transfected cells) diminished HDACI-mediated Mn-SOD2 induction and increased ROS accumulation, DNA damage, and apoptosis. The Mn-SOD2 mimetic TBAP (manganese(III)-tetrakis 4-benzoic acid porphyrin) prevented HDACI-induced ROS and NF-kappaB activation while dramatically attenuating DNA damage and cell death. In contrast, TRAF2 siRNA knockdown, targeting receptor-mediated NF-kappaB activation, blocked TNFalpha- but not HDACI-mediated NF-kappaB activation and lethality. Consistent with ROS-mediated DNA damage, LBH-589 exposure activated ATM (on serine 1981) and increased its association with NEMO. Significantly, siRNA NEMO or ATM knockdown blocked HDACI-mediated NF-kappaB activation, resulting in diminished MnSOD2 induction and enhanced oxidative DNA damage and cell death. In accord with the recently described DNA damage/ATM/NEMO pathway, SUMOylation site mutant NEMO (K277A or K309A) cells exposed to LBH-589 displayed diminished ATM/NEMO association, NEMO and p65/RelA nuclear localization/activation, and MnSOD2 up-regulation. These events were accompanied by increased ROS production, gamma-H2AX formation, and cell death. Together, these findings indicate that in human leukemia cells, HDACIs activate the cytoprotective NF-kappaB pathway through an ATM/NEMO/SUMOylation-dependent process involving the induction of ROS and DNA damage and suggest that blocking NF-kappaB activation via the atypical ATM/NEMO nuclear pathway can enhance HDACI antileukemic activity.
 ...
PMID:Histone deacetylase inhibitors activate NF-kappaB in human leukemia cells through an ATM/NEMO-related pathway. 2754 93

Transcription and replication of mitochondrial DNA (mtDNA) are regulated by nuclear DNA-encoded proteins that are targeted into mitochondria. A decrease in mtDNA copy number results in mitochondrial dysfunction, which may lead to insulin resistance and metabolic syndromes. We analyzed mitochondrial proteins that physically bind to human mitochondrial D-loop DNA using a shot-gun proteomics approach following protein enrichment by D-loop DNA-linked affinity chromatography. A total of 152 D-loop DNA binding proteins were identified by peptide sequencing using ultra high pressure capillary reverse-phase liquid chromatography/tandem mass spectrometry. Bioinformatic analysis showed that 68 were mitochondrial proteins, 96 were DNA/RNA/protein binding proteins and 114 proteins might form a complex via protein-protein interactions. Histone family members of H1, H2A, H2B, H3, and H4, were detected in abundance among them. In particular, histones H2A and H2B were present in the mitochondrial membrane as integral membrane proteins and not bound directly to mtDNA inside the organelle. Histones H1.2, H3 and H4 were associated with the outer mitochondrial membrane. Silencing of H2AX expression inhibited mitochondrial protein transport. Our data suggests that many mitochondrial proteins may reside in multiple subcellular compartments like H2AX and exert multiple functions.
 ...
PMID:Shot-gun proteomic analysis of mitochondrial D-loop DNA binding proteins: identification of mitochondrial histones. 2135 16