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)

Ionizing radiation and the topoisomerase II inhibitor, teniposide (VM-26) both increase levels of the cyclin dependent kinase inhibitor, p21(waf1/cip1) and promote dephosphorylation of the retinoblastoma tumor suppressor protein, Rb, in MCF-7 breast tumor cells, perturbations associated with suppression of the activity of the transcription factor, E2F. However, studies using an E2F binding site-luciferase reporter plasmid transfected into MCF-7 cells failed to demonstrate a reduction in E2F activity in response to VM-26 or to ionizing radiation. In contrast, E2F activity (both basal and E1A stimulated) could be suppressed by transfection with a plasmid expressing Rb, indicating that the capacity of E2F to bind to Rb and to be inactivated by Rb is functionally intact in MCF-7 cells. These findings in MCF-7 breast tumor cells suggest that E2F activity may not be directly susceptible to modulation by endogenous p21(waf1/cip1) and Rb.
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PMID:Ionizing radiation and teniposide increase p21(waf1/cip1) and promote Rb dephosphorylation but fail to suppress E2F activity in MCF-7 breast tumor cells. 928 98

Transforming growth factor-beta (TGF-beta) protects normal cells from etoposide-induced cell death, yet the mechanism has remained speculative. Studies have shown that etoposide modifies the activity of the topoisomerase IIalpha (topo IIalpha) enzyme, thereby causing DNA damage and inducing cell death. Expression of topo IIalpha is necessary for etoposide-induced cell death, and peak expression of topo IIalpha normally occurs during the G2 phase of the cell cycle. We predicted that by arresting growth in the G1 phase, TGF-beta1 would prevent the induction of topo IIalpha expression that normally occurs subsequent to the G1-S transition, thereby protecting cells from etoposide-induced cell death. Accordingly, we hypothesized that the inhibition of topo IIalpha expression by TGF-beta1 would be dependent on the ability of TGF-beta1 to arrest cell cycle progression in G1. Using mink lung epithelial cells (MvlLu), we found that TGF-beta1 decreases topo IIalpha mRNA expression, and the decrease occurs as cells begin to accumulate in the G1 phase of the cell cycle. Topo IIalpha protein expression decreases subsequent to the fall in mRNA expression. In contrast, topo IIalpha expression is not affected by TGF-beta1 in cells that fail to undergo G1 arrest because of inactivation of the retinoblastoma tumor suppressor protein (pRb) by the papillomavirus type 16 E7 protein. Our studies suggest that inhibition of topo IIalpha by TGF-beta1 is the principal mechanism that protects mink lung epithelial cells (Mv1Lu) from etoposide-induced toxicity. Furthermore, the inhibition of topo IIalpha protein expression by TGF-beta1 is dependent on pRb-mediated cell cycle arrest, suggesting that TGF-beta1 will not reduce the sensitivity of pRb-deficient cancers to etoposide.
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PMID:Inhibition of topoisomerase IIalpha expression by transforming growth factor-beta1 is abrogated by the papillomavirus E7 protein. 1115 1

The retinoblastoma tumor suppressor protein (RB) is targeted for inactivation in the majority of human tumors, underscoring its critical role in attenuating cellular proliferation. RB inhibits proliferation by repressing the transcription of genes that are essential for cell cycle progression. To repress transcription, RB assembles multiprotein complexes containing chromatin-modifying enzymes, including histone deacetylases (HDACs). However, the extent to which HDACs participate in transcriptional repression and are required for RB-mediated repression has not been established. Here, we investigated the role of HDACs in RB-dependent cell cycle inhibition and transcriptional repression. We find that active RB mediates histone deacetylation on cyclin A, Cdc2, topoisomerase IIalpha, and thymidylate synthase promoters. We also demonstrate that this deacetylation is HDAC dependent, since the HDAC inhibitor trichostatin A (TSA) prevented histone deacetylation at each promoter. However, TSA treatment blocked RB repression of only a specific subset of genes, thereby demonstrating that the requirement of HDACs for RB-mediated transcriptional repression is promoter specific. The HDAC-independent repression was not associated with DNA methylation or gene silencing but was readily reversible. We show that this form of repression resulted in altered chromatin structure and was dependent on SWI/SNF chromatin remodeling activity. Importantly, we find that cell cycle inhibitory action of RB is not intrinsically dependent on the ability to recruit HDAC activity. Thus, while HDACs do play a major role in RB-mediated repression, they are dispensable for the repression of critical targets leading to cell cycle arrest.
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PMID:Histone deacetylation of RB-responsive promoters: requisite for specific gene repression but dispensable for cell cycle inhibition. 1456 17

The retinoblastoma tumor suppressor protein (RB), a critical mediator of cell cycle progression, is functionally inactivated in the majority of human cancers, including prostatic adenocarcinoma. The importance of RB tumor suppressor function in this disease is evident because 25% to 50% of prostatic adenocarcinomas harbor aberrations in RB pathway. However, no previous studies challenged the consequence of RB inactivation on tumor cell proliferation or therapeutic response. Here, we show that RB depletion facilitates deregulation of specific E2F target genes, but does not confer a significant proliferative advantage in the presence of androgen. However, RB-deficient cells failed to elicit a cytostatic response (compared with RB proficient isogenic controls) when challenged with androgen ablation, AR antagonist, or combined androgen blockade. These data indicate that RB deficiency can facilitate bypass of first-line hormonal therapies used to treat prostate cancer. Given the established effect of RB on DNA damage checkpoints, these studies were then extended to determine the impact of RB depletion on the response to cytotoxic agents used to treat advanced disease. In this context, RB-deficient prostate cancer cells showed enhanced susceptibility to cell death induced by only a selected subset of cytotoxic agents (antimicrotubule agents and a topoisomerase inhibitor). Combined, these data indicate that RB depletion dramatically alters the cellular response to therapeutic intervention in prostate cancer cells and suggest that RB status could potentially be developed as a marker for effectively directing therapy.
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PMID:Retinoblastoma tumor suppressor status is a critical determinant of therapeutic response in prostate cancer cells. 1761 76

The regulation of DNA relaxation by topoisomerase 1 (TOP1) is essential for DNA replication, transcription, and recombination events. TOP1 activity is elevated in cancer cells, yet the regulatory mechanism restraining its activity is not understood. We present evidence that the tumor suppressor protein prostate apoptosis response-4 (Par-4) directly binds to TOP1 and attenuates its DNA relaxation activity. Unlike camptothecin, which binds at the TOP1-DNA interface to form cleavage complexes, Par-4 interacts with TOP1 via its leucine zipper domain and sequesters TOP1 from the DNA. Par-4 knockdown by RNA interference enhances DNA relaxation and gene transcription activities and promotes cellular transformation in a TOP1-dependent manner. Conversely, attenuation of TOP1 activity either by RNA interference or Par-4 overexpression impedes DNA relaxation, cell cycle progression, and gene transcription activities and inhibits transformation. Collectively, our findings suggest that Par-4 serves as an intracellular repressor of TOP1 catalytic activity and regulates DNA topology to suppress cellular transformation.
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PMID:Par-4 binds to topoisomerase 1 and attenuates its DNA relaxation activity. 1867 42

BRCA1-mutated breast cancer (BC) is responsible for approximately 25% of hereditary breast cancer cases. BRCA1 is a tumor suppressor protein regulating the cell cycle and DNA repair; therefore its dysfunctions play a significant role in carcinogenesis. BRCA1-mutated BC is associated with basal-like phenotype, lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in addition to frequent TP53 mutations and poor prognosis. Currently used criteria for genetic evaluation of BC for the risk of hereditary mutations are based on patients' age and family history, and therefore are prone to be imprecise or incomplete. This review discusses recently developed sets of immunohistochemical markers, promising independent markers (nestin, ALDH1, FOXO3, claudins, topoisomerase 1, EGFR) and their potential to be incorporated into clinical practice as a support tool in oncological counseling. This approach could be applied as a screening method for cost-effective selection of cases requiring genetic testing or adapted in pathology laboratories with limited access to molecular techniques. Although not all of the described predictor models have been validated yet, they could further improve the performance of BRCA1 screening methods in BC in the near future via increasing the accuracy of criteria for further genetic evaluation.
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PMID:Incorporating immunohistochemical markers into screening methods for BRCA1-mutated breast cancer. 3311 17