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)

Histone H2AX is required to maintain genomic stability in cells and to suppress malignant transformation of lymphocytes in mice. H2ax(-/-)p53(-/-) mice succumb predominantly to immature alphabeta T-cell lymphomas with translocations, deletions, and genomic amplifications that do not involve T-cell receptor (TCR). In addition, H2ax(-/-)p53(-/-) mice also develop at lower frequencies B and T lymphomas with antigen receptor locus translocations. V(D)J recombination is initiated through the programmed induction of DNA double-strand breaks (DSBs) by the RAG1/RAG2 endonuclease. Because promiscuous RAG1/RAG2 cutting outside of antigen receptor loci can promote genomic instability, H2ax(-/-)p53(-/-) T-lineage lymphomas might arise, at least in part, through erroneous V(D)J recombination. Here, we show that H2ax(-/-)p53(-/-)Rag2(-/-) mice exhibit a similar genetic predisposition as do H2ax(-/-)p53(-/-) mice to thymic lymphoma with translocations, deletions, and amplifications. We also found that H2ax(-/-)p53(-/-)Rag2(-/-) mice often develop thymic lymphomas with loss or deletion of the p53(+) locus. Our data show that aberrant V(D)J recombination is not required for rapid onset of H2ax/p53-deficient thymic lymphomas with genomic instability and that H2ax deficiency predisposes p53(-/-)Rag2(-/-) thymocytes to transformation associated with p53 inactivation. Thus, H2AX is essential for suppressing the transformation of developing thymocytes arising from the aberrant repair of spontaneous DSBs.
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PMID:Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations. 1904 71

The topoisomerase-I (topo-I) inhibitor topotecan, derivative of camptothecin, is the only registered drug for relapsed small cell lung cancer (SCLC). The histone deacetylase inhibitor vorinostat has shown preclinical and clinical antitumor activities in hematologic malignancies and solid tumors, including SCLC, and has recently been approved for the treatment of cutaneous T-cell lymphomas. In this study, we analyzed the antitumor effect of vorinostat combined with topotecan or camptothecin in topo-I inhibitor-sensitive H209 and inhibitor-resistant H526 SCLC cells. Simultaneous or sequential exposure (24 h delay) to either agent resulted in strong synergistic cytotoxic effect in both cell lines, as shown by calculating combination index, and confirmed by growth in soft agar. Combination treatments increased S-phase cell cycle arrest paralleled by apoptosis as measured by hypodiploid peak formation, Annexin V binding, DNA fragmentation, and mitochondria destruction. The apoptotic process was triggered by a caspase-dependent mechanism and can be ascribed to the phosphorylation of H2AX, a reporter of DNA double-strand breaks. These effects were paralleled by an increase of topo-I/DNA covalent complexes induced by combination treatment and suggest a potentiation by vorinostat of topotecan-induced DNA damage. Finally, oxidative injury played a significant functional role in the observed enhanced lethality because coadministration of the antioxidant N-acetyl-l-cysteine blocked reactive oxygen species generation, apoptosis, and mitochondria destruction induced by the vorinostat/topotecan combination. To our knowledge, this is the first demonstration of a synergistic antitumor effect between topotecan and vorinostat in SCLC. Because no well-established treatment is available for recurrent SCLC patients, our results indicate that this drug combination should be explored clinically.
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PMID:Synergistic antitumor effect between vorinostat and topotecan in small cell lung cancer cells is mediated by generation of reactive oxygen species and DNA damage-induced apoptosis. 1988 47