Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the promoter of the human type-I-DNA topoisomerase gene (hTOP1) for regions protected against DNase I digestion by nuclear proteins from HeLa or from adenovirus-transformed 293 cells. We identified ten protected DNA sequences within 580 bp of DNA upstream of the transcriptional-start sites and one additional site, which is located between the two clusters of transcriptional-start sites. Several of these protein-binding sites have significant similarities to recognition sequences of known transcription factors including factors Sp1, octamer transcription factor, cAMP-responsive-element-binding protein (CREB/ATF), NF-kappa B and members of the Myc-related family of basic/helix-loop-helix/leucine-zipper proteins. Other protein-binding sites show less or no similarities to known consensus sequences. We investigated the physiological significance of these protein-binding sites using a set of deletion and nucleotide-exchange mutants. We conclude that the expression of the hTOP1 gene is regulated by a complex network of negatively and positively acting transcription factors.
 ...
PMID:The promoter region of the human type-I-DNA-topoisomerase gene. Protein-binding sites and sequences involved in transcriptional regulation. 822 37

DNA topoisomerase inhibitors are effective chemotherapeutic agents on several solid tumor cells. They induce a specific signaling cascade that executes an active cell death process (apoptosis), including caspase activation, and the blockage of the signaling is associated with drug-resistance of tumor cells. However, little is known about the initial signal transduction induced by the agents. In the present study, we screened genes that are initially upregulated in caspase-independent manner. We found that the activating transcription factor 3 (ATF3) protein, a repressor of cyclic-AMP responsive element (CRE)-dependent transcription, was strongly induced among CRE-BP/ATF members and subsequently accumulated in nuclei following camptothecin or etoposide treatment. During induction of apoptosis, the accumulation and the nuclear translocation of ATF3 coincided with the activation of caspase protease and were not inhibited by the broad caspase inhibitor Z-VAD-fmk, indicating that ATF3 induction is not a downstream event of caspase activation. When stably or transiently overexpressed, ATF3 markedly accelerated the drug-induced apoptosis and enhanced caspase protease activation. ATF3 strongly downregulated CRE-dependent transcription, while ATF3 did not affect the expression levels of Bcl-2, Bcl-x, or Bax. Our present results indicate that ATF3 plays a critical role in accelerating caspase protease activation and apoptosis. Since CRE-dependent transcription functions as cell survival signaling, ATF3 could control the upstream signaling of apoptosis by repressing CRE-dependent gene expression of cell survival factors.
 ...
PMID:Involvement of transcriptional repressor ATF3 in acceleration of caspase protease activation during DNA damaging agent-induced apoptosis. 1147 62

DNA topoisomerase IIalpha (Topo IIalpha) is regulated in late S phase-dependent manner. To identify late S phase-dependent cis-acting elements of Topo IIalpha gene, we have investigated the synchronized HeLa cells with chloramphenicol acetyltransferase and DNase I footprinting assays. The level of Topo IIalpha mRNA increased after release from aphidicolin block and reached a maximum in 8h (late S phase) in HeLa cells, and Topo II unknotting activity was also in parallel with the level of Topo IIalpha mRNA. The late S phase-regulatory element was found to be located in the region containing ATF-binding element between -290 and -90bp and the region was required for a maximal stimulation during late S phase. DNase I footprinting assay showed that ATF-binding element and novel cis-acting element (Topo IIalpha-specific sequence) were the principal protein-binding sites and the proteins interacting with these elements were induced during late S phase. One DNA-protein complex was formed by DNA mobility shift assay when ATF-binding site was incubated with nuclear extract prepared from late S phase cells, but no protein bound in non-S phase cells. Taken together, these results suggest that ATF may be essential transacting factor for maximal expression of Topo IIalpha gene during late S phase in HeLa cells.
 ...
PMID:ATF is important to late S phase-dependent regulation of DNA topoisomerase IIalpha gene expression in HeLa cells. 1210 51

HTLV-1 is the etiological agent of adult T-cell leukemia (ATL), the neurological syndrome TSP/HAM and certain other clinical disorders. The viral Tax protein is considered to play a central role in the process leading to ATL. Tax modulates the expression of many viral and cellular genes through the CREB/ATF-, SRF- and NF-kappaB-associated pathways. In addition, Tax employs the CBP/p300 and p/CAF co-activators for implementing the full transcriptional activation competence of each of these pathways. Tax also affects the function of various other regulatory proteins by direct protein-protein interaction. Through these activities Tax sets the infected T-cells into continuous uncontrolled replication and destabilizes their genome by interfering with the function of telomerase and topoisomerase-I and by inhibiting DNA repair. Furthermore, Tax prevents cell cycle arrest and apoptosis that would otherwise be induced by the unrepaired DNA damage and enables, thereby, accumulation of mutations that can contribute to the leukemogenic process. Together, these capacities render Tax highly oncogenic as reflected by its ability to transform rodent fibroblasts and primary human T-cells and to induce tumors in transgenic mice. In this article we discuss these effects of Tax and their apparent contribution to the HTLV-1 associated leukemogenic process. Notably, however, shortly after infection the virus enters into a latent state, in which viral gene expression is low in most of the HTLV-1 carriers' infected T-cells and so is the level of Tax protein, although rare infected cells may still display high viral RNA. This low Tax level is evidently insufficient for exerting its multiple oncogenic effects. Therefore, we propose that the latent virus must be activated, at least temporarily, in order to elevate Tax to its effective level and that during this transient activation state the infected cells may acquire some oncogenic mutations which can enable them to further progress towards ATL even if the activated virus is re-suppressed after a while. We conclude this review by outlining an hypothetical flow of events from the initial virus infection up to the ultimate ATL development and comment on the risk factors leading to ATL development in some people and to TSP/HAM in others.
 ...
PMID:Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity. 1531 Apr 5