Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that the histone-modifying enzymes histone acetyltransferase (HAT) and histone deacetylase (HDAC) are involved in transcriptional activation and repression, respectively. However, little is known about the endogenous genes that are regulated by these enzymes or how specificity is achieved. In the present report, we demonstrate that HAT and HDAC activities modulate transcription of the P-glycoprotein-encoding gene, MDR1. Incubation of human colon carcinoma SW620 cells in 100-ng/ml trichostatin A (TSA), a specific HDAC inhibitor, increased the steady-state level of MDR1 mRNA 20-fold. Furthermore, TSA treatment of cells transfected with a wild-type MDR1 promoter/luciferase construct resulted in a 10- to 15-fold induction of promoter activity. Deletion and point mutation analysis determined that an inverted CCAAT box was essential for this activation. Consistent with this observation, overexpression of p300/CREB binding protein-associated factor (P/CAF), a transcriptional coactivator with intrinsic HAT activity, activated the wild-type MDR1 promoter but not a promoter containing a mutation in the CCAAT box; deletion of the P/CAF HAT domain abolished activation. Gel shift and supershift analyses identified NF-Y as the CCAAT-box binding protein in these cells, and cotransfection of a dominant negative NF-Y expression vector decreased the activation of the MDR1 promoter by TSA. Moreover, NF-YA and P/CAF were shown to interact in vitro. This is the first report of a natural promoter that is modulated by HAT and HDAC activities in which the transcription factor mediating this regulation has been identified.
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PMID:Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y. 963 21

Depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7[(Z)-ethylideno]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone], a novel histone deacetylase (HDAC) inhibitor, previously was reported to be a P-glycoprotein (Pgp) substrate. We now expand the investigation to demonstrate that FK228 is a substrate for Pgp and multidrug resistance-associated protein 1 (MRP1). Transport of FK228 across the Caco-2 cell monolayer in apical to basolateral (AP-->BL) and basolateral to apical (BL-->AP) directions in the absence and presence of Pgp and MRP inhibitors were investigated. An in vitro uptake study in human red blood cells (RBCs) and a cytotoxicity assay in MRP1(-) HL60 and MRP1(+) HL60Adr cells were conducted to show that FK228 is an MRP1 substrate. An FK228-resistant cell line (HCT15R) was developed from HCT15 colon carcinoma and characterized using a 70-oligomer cDNA microarray, reverse transcription-polymerase chain reaction, Western blot analysis, histone acetyltransferase (HAT) and HDAC activity assays, and cytotoxicity assays. FK228 showed a nearly unidirectional flux across the Caco-2 cell monolayer, with the BL-->AP apparent permeability coefficient (P(app)) 32 times that of AP-->BL without apparent saturation. Pgp inhibition decreased the BL-->AP P(app) and increased the AP-->BL P(app). RBC showed a concentration-dependent uptake and saturable efflux of FK228. HL60Adr cells were 4-fold more resistant to FK228 than HL60 cells, and the resistance was reversed by MRP inhibition. Up-regulation of Pgp, but not changes of MRPs or HAT/HDAC enzymatic activities, was the major mechanism for the acquired FK228 resistance. These studies demonstrate that FK228 is a substrate for Pgp and MRP1, and reversible Pgp up-regulation is predominantly involved in FK228 resistance in vitro.
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PMID:Efflux of depsipeptide FK228 (FR901228, NSC-630176) is mediated by P-glycoprotein and multidrug resistance-associated protein 1. 1563 44

In this study we have investigated hyaluronan (HA)-mediated CD44 (an HA receptor) interactions with p300 (a histone acetyltransferase) and SIRT1 (a histone deacetylase) in human breast tumor cells (MCF-7 cells). Specifically, our results indicate that HA binding to CD44 up-regulates p300 expression and its acetyltransferase activity that, in turn, promotes acetylation of beta-catenin and NFkappaB-p65 leading to activation of beta-catenin-associated T-cell factor/lymphocyte enhancer factor transcriptional co-activation and NFkappaB-specific transcriptional up-regulation, respectively. These changes then cause the expression of the MDR1 (P-glycoprotein/P-gp) gene and the anti-apoptotic gene Bcl-x(L) resulting in chemoresistance in MCF-7 cells. Our data also show that down-regulation of p300, beta-catenin, or NFkappaB-p65 in MCF-7 cells (by transfecting cells with p300-, beta-catenin-, or NFkappaB-p65-specific small interfering RNA) inhibits the HA/CD44-mediated beta-catenin/NFkappaB-p65 acetylation and abrogates the aforementioned transcriptional activities. Subsequently, there is a significant decrease in both MDR1 and Bcl-x(L) gene expression and an enhancement in caspase-3 activity and chemosensitivity in the breast tumor cells. Further analyses indicate that activation of SIRT1 (deacetylase) by resveratrol (a natural antioxidant) induces SIRT1-p300 association and acetyltransferase inactivation, leading to deacetylation of HA/CD44-induced beta-catenin and NFkappaB-p65, inhibition of beta-catenin-T-cell factor/lymphocyte enhancer factor and NFkappaB-specific transcriptional activation, and the impairment of MDR1 and Bcl-x(L) gene expression. All these multiple effects lead to an activation of caspase-3 and a reduction of chemoresistance. Together, these findings suggest that the interactions between HA/CD44-stimulated p300 (acetyltransferase) and resveratrol-activated SIRT1 (deacetylase) play pivotal roles in regulating the balance between cell survival versus apoptosis, and multidrug resistance versus sensitivity in breast tumor cells.
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PMID:Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells. 1904 49