Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cultured human epidermal keratinocytes were used as a model system for testing compounds with potential therapeutic effect against hyperproliferative skin disorders. We have investigated whether each test compound caused direct damage to the DNA or inhibited DNA repair and/or seminconservative replication of DNA, as well as its effect on the overall rate of protein synthesis and on expression of specific keratin genes. The following compounds were studied: (a) inhibitors of DNA polymerase alpha [aphidicolin and its derivative aphidicolin glycine], (b) inhibitors of topoisomerases [novobiocin, nalidixic acid, teniposide, etoposide, and 4'-(9-acridylamine) methanesulfon-m-anisidide], (c) modifiers of chromatin structure [sodium butyrate, 3-aminobenzamide, and nicotinamide], (d) inhibitors of calmodulin activation and protein kinase C [chlorpromazine and trifluoperazine]; and (e) drugs used in clinical dermatology [anthralin, fluocinolone acetonide, ketoconazole, and hydroxyurea]. The compounds were tested at concentrations at which they were known from the literature to be effective in their respective actions. Among the groups of compounds studied, the topoisomerase inhibitors were particularly interesting since they caused no detectable damage to DNA but exhibited maximal inhibitory effect on replication combined with minimal inhibition of DNA repair. In addition most of the topoisomerase inhibitors, particularly novobiocin, changed the pattern of gene expression by inhibiting the synthesis of certain keratins and inducing a Mr 67,000 protein in the prekeratin fraction. These properties combined with minimal systemic side effects may encourage the clinical exploration of some topoisomerase inhibitors for antiproliferative therapy of skin disorders.
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PMID:Comparative effects of growth inhibitors on DNA replication, DNA repair, and protein synthesis in human epidermal keratinocytes. 242 88

The progression of mammalian gametogenesis requires a precise balance between cell-cycle activities and elimination of defective gametogenic cells to ensure the perpetuation of species. Both spermatogonia and oogonia are stem cell populations committed to meiosis with the aim of generating haploid gametes for fertilization. At puberty, mitotically dividing spermatogonial cell cohorts maintain the ability of cell renewal and occupy niches in the seminiferous tubule. In contrast, mitotically dividing oogonial cell cohorts produced in the fetal ovary, are exclusively committed to meiosis and produce primordial follicles housing a primary oocyte surrounded by somatic follicular cells. A consistent physiological event during mammalian gametogenesis is the disposal of spermatogenic cells by apoptosis and ovarian follicles by atresia. Cyclin-dependent kinases (Cdks) and their cyclin partners coordinate the activities of the cell cycle. An additional cell-cycle regulatory component is the centrosome. The centrosome harbors regulatory proteins controlling the normal progression of the cell cycle. Changes in individual centrosome proteins can lead to cell-cycle arrest and a decrease in the genomic protective function of p53 that promotes apoptosis. Disruption of cyclin A1, Cdk2, and Cdk4 expression in transgenic mice results in infertility and gonadal atrophy. Cdk-cyclin complexes interact with regulatory proteins, which may fine-tune the activities of the complex. One of the many regulatory proteins is p12, a 115 amino acid growth suppressor polypeptide designated p12(CDK2AP1), partner of Cdk2 and with binding affinity to DNA polymerase alpha/primase. Overexpression of p12 is associated with testicular and ovarian atrophy without affecting fertility. Ectopic expression of p12 was driven by the keratin 14 promoter. Keratin 14 is the pairing partner of keratin 5 and both keratins are expressed in testis. The efficiency of keratin promoters in driving ectopic gonadal gene expression, the association of gonadal atrophy with the ectopic expression of a Cdk2 regulatory protein and the centrosome, as a reservoir of cell-cycle regulatory proteins, open new experimental opportunities to address still lingering questions concerning cell differentiation and division during mammalian gametogenesis.
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PMID:Cell-cycle regulation and mammalian gametogenesis: a lesson from the unexpected. 1670 69