Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Connexin32 (Cx32) is the major gap junction forming protein in liver and lack of functional Cx32 enhances hepatocarcinogenesis. Many tumour-promoting agents block gap junctional intercellular communication, which may favour clonal expansion of neoplastic cells. We recently demonstrated that liver tumourigenesis is accelerated in Cx32-wild-type but not in Cx32-null mice by the model tumour promoter phenobarbital (PB). In the present study, male Cx32-wild-type and Cx32-null mice were treated with a single injection of 90 micro g/g body wt of N-nitrosodiethylamine (DEN) at 6 weeks of age and were subsequently kept on a diet containing the peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) or on control diet. Thirty-eight weeks after DEN treatment, mice were killed, frozen liver sections were prepared and (pre)-neoplastic lesions were identified by alterations in glucose-6-phosphatase (G-6-Pase) and glutamine synthetase (GS) staining. G-6-Pase-deficient lesions were generally small in size and were observed in all groups of mice. Large focal pre-neoplastic and benign neoplastic lesions, however, which demonstrated increased rather than decreased activity in G-6-Pase were exclusively present in DEN/Wy-14,643-treated mice. G-6-Pase-positive lesions were strongly promoted by Wy-14,643, both in Cx32-wild-type and Cx32-null mice without significant difference in response between mice of the two genotypes. This contrasts G-6-Pase-negative lesions and lesions over-expressing GS, which were both increased by WY-14,643 treatment in number and size in Cx32-wild-type but not in Cx32-null mice. GS-positive lesions from WY-14,643-treated mice harboured beta-catenin mutations, a hallmark of lesions selected during promotion by PB, while G-6-Pase-positive lesions, which displayed negative or diffuse GS staining, did not show beta-catenin mutations. Our results demonstrate significant differences between mouse liver lesions of differing phenotype and genotype in their response towards selection by Wy-14,643 during the promotional phase of hepatocarcinogenesis.
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PMID:WY-14,643-mediated promotion of hepatocarcinogenesis in connexin32-wild-type and connexin32-null mice. 1281 87

Connexin32 (Cx32) is the major gap junction forming protein in liver. Mice deficient in Cx32 demonstrate enhanced liver tumor formation, but are resistant to promotion of hepatocarcinogenesis by the model tumor promoter phenobarbital (PB). Here, we re-evaluate data on the number and sizes of glucose-6-phosphatase (G6Pase)-deficient liver lesions, both in Cx32-wildtype (WT) and Cx32-null male mice, obtained from two earlier experiments with similar protocols but paradoxical outcomes. In these experiments, enzyme-altered lesions were induced in mice of both strains by a single injection of N-nitrosodiethylamine (DEN) at age 6 weeks with a dose of 90 microg/g body weight (experiment 1) or at age 2 weeks with 10 microg/g body weight (experiment 2). Three weeks after DEN treatment groups of mice (sub-divided by Cx32 status) were also started on a PB-containing (0.05%) diet to test the responsiveness of the lesions to the tumor promoter. Additionally, for experiment 1, tumors were analyzed for the presence of Ha-ras and beta-catenin mutations. Based on the mutational analysis and the mathematical analysis of the G6Pase-deficient lesions, the two studies are consistent with the hypothesis of two types of lesions, 'late-type' lesions which are mainly characterized by beta-catenin mutations, and 'early-type' lesions that are frequently (but not exclusively) Ha-ras mutated. This concept affords an explanation as to the differential response seen in the two experiments with regard to Cx32 status and the role of PB as a tumor promoter (experiment 1) or inhibitor (as in experiment 2). Our findings also underscore the importance of the timing (6 weeks versus 2 weeks) of the genotoxic insult in relation to the developmental stage of the liver and the importance of clonal selection during tumor promotion.
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PMID:Modulation of liver tumorigenesis in Connexin32-deficient mouse. 1568 Apr 1