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

Human Embryonic Stem Cells (hESCs) have a great therapeutic potential in regenerative medicine, but the precise molecular mechanisms by which hESCs maintain or regulate their characteristics remain largely unknown. Since protein-protein interaction is vitally important in regulating hESCs, we utilized a network-based bioinformatics analysis in order to learn what and how specific proteins interact with each other. By combining protein-protein interaction data and a collection of genes over-expressed in hESCs, we constructed a protein interaction network using a breadth-first search algorithm. This scale-free network which is significantly larger than networks generated by random samplings, illustrates how these hESC-enriched proteins might interact with each other in hESCs. Of the top 5% highly connected nodes (corresponding to 21 proteins including MYC, H2AFX, RUVBL1, DDX18, CDC2, HDAC2 and HIST1H4C) presumably critical for determining the fate of hESCs, nearly half are known to be regulated by NANOG/SOX2/MYC. This underscores importance of these transcription factors in hESCs. In addition, in silico cis-element analysis suggests that NF-Y may be an important transcription factor regulating many of these hub proteins (high connected nodes) in hESCs. To further abstract the functional significance, directly connected proteins were matched to and grouped by gene ontology (GO) terms in molecular function category. Sixty- six interacting GO-GO terms paired through protein interactions were found over-represented in hESCs. This functional enrichment may be essential for understanding molecular characteristics in hESCs. Collectively, we analyzed hESC-enriched genes based on protein-protein interaction data, from which an hESC-enriched protein interaction network was constructed and a network of molecular functional terms was also identified. The results of this analysis, on the systems level, may shed new light to further our understanding of hESCs.
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PMID:Enriching protein-protein and functional interaction networks in human embryonic stem cells. 1942 9

We previously demonstrated that the PPARgamma agonist Troglitazone (TRG), a potent antiproliferative agent, in combination with the anthracycline antibiotic Doxorubicin (DOX), is an effective killer of multiple drug resistant (MDR) human cancer cells. Cell killing was accompanied by increased global histone H3 acetylation. Presently, we investigated the epigenetic and cell killing effects of TRG in estrogen receptor (ER) positive MCF7 breast cancer cells. MCF7 cells were treated with the Thiazolidinediones (TZDs) TRG and Ciglitazone (CIG), the non-TZD PPARgamma agonist 15PGJ2, and the histone deacetylase inhibitors (HDACi's) Trichostatin A (TSA), sodium butyrate and PXD101. Using MTT cell viability assays, Western analyzes and mass spectrometry, we showed a dose-dependent increase in cell killing in TRG and HDACi treated cells, that was associated with increased H3 lysine 9 (H3K9) and H3K23 acetylation, H2AX and H3S10 phosphorylation, and H3K79 mono- and di-methylation. These effects were mediated through an ER independent pathway. Using HDAC activity assays, TRG inhibited HDAC activity in cells and in cell lysates, similar to that observed with TSA. Furthermore, TRG and TSA induced a slower migrating HDAC1 species that was refractory to HDAC2 associations. Lastly, TRG and the HDACi's decreased total and phosphorylated AKT levels. These findings suggest that TRG's mode of killing may involve downregulation of PI3K signaling through HDAC inhibition, leading to increased global histone post-translational modifications.
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PMID:Troglitazone inhibits histone deacetylase activity in breast cancer cells. 1969 29

Using a systems biology approach to prioritize potential points of intervention in ovarian cancer, we identified the lysine rich coiled-coil 1 (KRCC1), as a potential target. High-grade serous ovarian cancer patient tumors and cells express significantly higher levels of KRCC1 which correlates with poor overall survival and chemoresistance. We demonstrate that KRCC1 is predominantly present in the chromatin-bound nuclear fraction, interacts with HDAC1, HDAC2, and with the serine-threonine phosphatase PP1CC. Silencing KRCC1 inhibits cellular plasticity, invasive properties, and potentiates apoptosis resulting in reduced tumor growth. These phenotypes are associated with increased acetylation of histones and with increased phosphorylation of H2AX and CHK1, suggesting the modulation of transcription and DNA damage that may be mediated by the action of HDAC and PP1CC, respectively. Hence, we address an urgent need to develop new targets in cancer.
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PMID:KRCC1: A potential therapeutic target in ovarian cancer. 3190 25