Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to cisplatin (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1.
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PMID:Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1. 2305 66

Claudin-19 is the major claudin in the tight junctions of the retinal pigment epithelium (RPE). Claudin-3 is also uniformly expressed albeit in lesser amounts. Besides modulating transepithelial diffusion, claudins modulate gene expression. The absence of claudin-19 and claudin-3 in the RPE cell lines, ARPE-19 and hTERT-RPE-1, provide an opportunity to examine whether exogenous claudins regulate gene expression in the absence of tight junctions. Quantitative RT-PCR was used to compare gene expression in ARPE-19 and hTERT-RPE-1 with that of highly differentiated, human fetal RPE. Claudin-19 and claudin-3 were exogenously expressed using an adenoviral vector. The transepithelial electrical resistance (TER) was measured using Endohm electrodes, and the effects of claudin on the actin cytoskeleton were determined by immunocytochemistry. The effect of claudin on gene expression was examined by quantitative RT-PCR and western blotting. Aside from claudin-19 and claudin-3, ARPE-19 and hTERT-RPE-1 expressed most junction-associated mRNAs in amounts comparable to human fetal RPE, but some RPE signature and maturation genes were under-expressed. Unlike ARPE-19, hTERT-RPE-1 failed to form tight junctions or develop a TER. Claudins exogenously expressed in hTERT-RPE-1 failed to crystalize an apical junctional complex. Actin filaments were not redistributed from stress fibers to cortical bands, and a TER was not established. In hTERT-RPE-1, claudins were found only in internal vesicular-like structures. Nonetheless, claudins increased the expression of the mRNAs for a collection of RPE-enriched proteins. Claudin-19 and claudin-3 had different effects on gene and protein expression indicating activation of overlapping, but distinct, signaling pathways. A major difference was the ability of claudin-19 to affect steady-state levels of ADAM9 and tyrosinase in ARPE-19. In conclusion, claudins can increase the barrier function of a pre-existing apical junctional complex, but on its own it cannot recruit tight junction proteins to form a complex de novo. Many effects of claudin on gene expression did not require an association with the apical junctional complex. Although claudin-19 shared many effects with claudin-3, claudin-19 exerted unique effects on the maturation of RPE.
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PMID:Claudins regulate gene and protein expression of the retinal pigment epithelium independent of their association with tight junctions. 3271 83