Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoic acid (RA)-associated differentiation of murine F9 teratocarcinoma stem cells results in dramatic changes in gene expression. The cellular gene encoding the B1 subunit of the extracellular matrix protein laminin is transcriptionally activated by RA, and its transcription is further enhanced by N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate (Bt2cAMP) during the differentiation of F9 stem cells into extraembryonic parietal endoderm cells. We now report that expression vectors encoding the human RA receptors RAR-alpha, RAR-beta, and RAR-gamma can activate chloramphenicol acetyltransferase (CAT) expression from laminin B1 promoter/CAT expression vectors (e.g., p1.6LAMCAT) in RA-treated F9 cells, as measured in a transient transfection assay. Bt2cAMP does not further enhance the RA-associated increase in CAT activity. Through the use of deletion and mutation analyses, the RA-responsive element (RARE) of the murine laminin B1 gene has been defined as a 46-base-pair element between -477 and -432 of the laminin B1 5' flanking region. Insertion of a region of DNA containing this RARE in either orientation into a thymidine kinase promoter/CAT expression vector causes CAT expression to be activated 5- to 9-fold by the cotransfected human RAR-alpha or RAR-beta constructs in RA-treated F9 cells, and this RARE also functions in human HeLa cells. In contrast, this RARE in the p1.6LAMCAT vector does not activate CAT expression when cotransfected into F9 stem cells with the c-erbA gene in the presence of thyroid hormone. This suggests that the laminin B1 gene is activated by RA but not by thyroid hormone in vivo.
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PMID:A retinoic acid-responsive element is present in the 5' flanking region of the laminin B1 gene. 255 99

Expression vectors have been constructed for a region of the human retinoic acid receptor-alpha (hRAR-alpha) and transferred into F9 embryonal carcinoma (EC) cells. When the vectors are overexpressed in F9 cells, clones can be selected for resistance to retinoic acid-induced differentiation. This effect is obtained even when the hRAR-alpha region is expressed as a beta-galactosidase fusion protein. Using the beta-galactosidase component of the fusion protein as a marker, overexpression of the fusion protein has been correlated with the retinoic acid-resistance effect. The clones resistant to retinoic acid no longer exhibit the normal retinoic acid induction of endo B cytokeratin, laminin B-1, and tissue plasminogen activator mRNAs observed with normal F9 cells. Retinoic acid induction of type IV alpha-1 collagen and Hox-1.3 RNAs is observed with these clones. When transfected with a thyroid receptor DNA-binding sequence (TRE)/thymidine kinase promoter/luciferase construct, the retinoic acid-resistant clones do not yield the same retinoic acid-induced level of luciferase obtained with F9 cells. It is hypothesized that the RAR vectors are interfering with endogenous RAR(s) in a dominant-negative manner to inhibit retinoic acid-induced differentiation of F9 EC cells.
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PMID:Retinoic acid receptor expression vector inhibits differentiation of F9 embryonal carcinoma cells. 255 44

Retinyl methyl ether (RME) is known to prevent the development of mammary cancer. However, the mechanism by which RME exerts its anticancer effect is presently unclear. The diverse biological functions of retinoids, the vitamin A derivatives, are mainly mediated by their nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARs and RXRs are ligand-dependent transcriptional factors that either activate gene transcription through their binding to retinoic acid response elements or repress transactivation of genes containing the activator protein 1 (AP-1) binding site. Previous studies demonstrated that RME can modulate transcriptional activity of retinoid receptors on retinoic acid response elements, suggesting that regulation of retinoid receptor activity may mediate the anticancer effect of RME. In this study, we present evidence that RME can down-regulate AP-1 activity induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, insulin, growth factors, and the nuclear proto-oncogenes c-Jun and c-Fos. Transient transfection assays demonstrate that inhibition of AP-1 activity occurs on the human collagenase promoter containing an AP-1 binding site or the thymidine kinase promoter linked with an AP-1 binding site. In HeLa cells, the inhibition is observed when RAR-alpha and/or RXR-alpha but not RAR-beta or RAR-gamma expression vectors are cotransfected, whereas the endogenous retinoid receptors in breast cancer cells T-47D and ZR-75-1 were sufficient to confer the inhibition by RME. Furthermore, using gel retardation assay, we show that 12-O-tetradecanoylphorbol-13-acetate- and epidermal growth factor-induced AP-1 binding activity in breast cancer cells is inhibited by RME. These results suggest that one of the mechanisms by which RME prevents cancer development may be due to the repression of AP-1-responsive genes.
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PMID:Retinyl methyl ether down-regulates activator protein 1 transcriptional activation in breast cancer cells. 927 11