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)

Vascular endothelial cells regulate vascular tonus, growth, and angiogenesis in response to mechanical stresses. ATP release is one of well-known mechanosensitive responses in endothelial cells. Released ATP induces Ca(2+) responses and nitric oxide production in neighboring cells in an auto/paracrine manner. Mechanosensitive and agonist-induced ATP releases are also observed in other cell types, but the cellular mechanisms and pathways of ATP release are largely unknown. Reported candidates for ATP release pathways are ABC proteins including P-glycoprotein and CFTR, exocytosis of ATP-containing vesicles, and ATP-permeable anion channels. In vascular endothelium, vesicular exocytosis, volume-regulated anion channels (VRAC), and connexin hemichannels have been reported as candidates for ATP release pathways. We found that VRAC inhibitors suppressed hypotonic stress-induced ATP release in bovine aortic endothelial cells. Furthermore, extracellular ATP suppressed VRAC current in a voltage dependent manner, which could be fitted to the permeation-blocker model with a Kd(0) of 1 mM and delta value of 0.41. However, it should be noted that VRAC is probably not the only pathway for ATP release in the endothelium, because basal ATP release was not inhibited by VRAC inhibitors. Further investigations are definitely warranted to clarify the details and therapeutic significance of mechanosensitive ATP release in the endothelium.
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PMID:[ATP release pathways in vascular endothelial cells]. 1517 80

We have reported that connexin (Cx) 32 gene, a member of gap junction protein family, acts as a tumor suppressor gene in human renal cell carcinoma (RCC). Of solid tumors, RCC is one of the most chemoresistant cancers, and there is no effective cancer chemotherapy against RCC at present. In this study, we examined if the combination of Cx32-dependent tumor-suppressive effect and vinblastine (VBL), a chemotherapeutic agent which has been utilized for clinical RCC treatment, could be effective in enhancing the sensitivity of RCC to VBL treatment. Cx32 expression in a human metastatic RCC cell (Caki-1 cell) significantly enhanced in vitro and in vivo VBL-induced cytotoxicity on the cell. Cx32 expression in the RCC cells potentiated VBL-induced apoptosis compared to the Cx32-negative RCC cells in vitro as well as in vivo. The enhancing apoptosis in the RCC cells by Cx32 mainly depended on the decrease of P-glycoprotein (P-gp), a multidrug resistance gene-1 (MDR-1) product responsible for reduction of VBL accumulation into the cells. We also observed that silencing of Cx32 by short interfering RNA (siRNA) treatment elevated the level of P-gp in Caki-1 cells and that inhibition of P-gp function enhanced VBL-induced apoptosis in the RCC cells. These results suggest that Cx32 is effective to enhance VBL-induced cytotoxicity in Caki-1 cells via the reduction of P-gp. Overall, it seems that the combination of Cx32-dependent tumor-suppressive effect and VBL is promising as a new cancer therapy against RCC.
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PMID:Connexin 32 potentiates vinblastine-induced cytotoxicity in renal cell carcinoma cells. 1718 40

Inositol 1,4,5-trisphosphate (IP(3)) is an important second messenger that can trigger a Ca(2+) wave prolongated between cells. This intercellular signaling was found defective in some gap junction connexin deafness mutants. In this study, the mechanism underlying IP(3) intercellular signaling in the cochlea was investigated. A gap junction channel is composed of two hemichannels. By using a fluorescence polarization technique to measure IP(3) concentration, the authors found that IP(3) could be released by gap junction hemichannels in the cochlea. The IP(3) release was increased about three- to fivefold by the reduction of extracellular Ca(2+) concentration or by mechanical stress. This incremental release could be blocked by gap junction blockers but not eliminated by a purinergic P2x receptor antagonist and verapamil, which is a selective P-glycoprotein inhibitor inhibiting the ATP-binding cassette transporters. The authors also found that IP(3) receptors were extensively expressed in the cochlear sensory epithelium, including on the cell surface. Extracellular application of IP(3) could trigger cellular Ca(2+) elevation. This Ca(2+) elevation was eliminated by the gap junction hemichannel blocker. These data reveal that IP(3) can pass through hemichannels acting as an extracellular mediator to participate in intercellular signaling. This hemichannel-mediated extracellular pathway may play an important role in long-distance intercellular communication in the cochlea, given that IP(3) only has a short lifetime in the cytoplasm.
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PMID:Hemichannel-mediated inositol 1,4,5-trisphosphate (IP3) release in the cochlea: a novel mechanism of IP3 intercellular signaling. 1897 96

Enforced expression of connexin (Cx) 32 gene, a member of gap junction gene family and a tumor suppressor gene in human renal cell carcinoma (RCC), enhanced vinblastine (VBL)-induced cytotoxicity on RCC cells, due to the suppression of multidrug resistance 1 (MDR1) gene product, P-glycoprotein (P-gp). Also, Cx32 gene in RCC is silenced by hypermethylation of CpG islands in a promoter region of the Cx gene. In this study, we investigated if a DNA demethylating agent, 5-aza-2'-deoxycytidine (5-Aza) could enhance susceptibility of RCC cells (Caki-1) to VBL. We found that 5-Aza treatment up-regulated Cx32 in Caki-1 cells, and the induction of the Cx led to the suppression of P-gp through inhibition of Src and subsequent activation of c-Jun NH(2)-terminal kinase (JNK). Moreover, increased transcription activity of c-Jun by the JNK activation contributed to the down-regulation of MDR1, thus indicating a central role of JNK signalling to suppress P-gp level in 5-Aza-treated Caki-1 cells. Chemical sensitivity to VBL in Caki-1 cells was increased by 5-Aza pre-treatment, and this effect was abrogated by short interfering RNA (siRNA)-mediated knockdown of Cx32. Furthermore, co-treatment of 5-Aza or a P-gp inhibitor with VBL drastically enhanced JNK activation comparing to only VBL treatment in Caki-1 cells. These results suggest that the restoration of Cx32 by 5-Aza pre-treatment improves chemical tolerance on VBL in Caki-1 cells and that the JNK activation is a key factor to induce the effect.
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PMID:Up-regulation of connexin 32 gene by 5-aza-2'-deoxycytidine enhances vinblastine-induced cytotoxicity in human renal carcinoma cells via the activation of JNK signalling. 2051 Feb 7