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)

Theaflavin (TF-1), theaflavin-3-monogallate and theaflavin-3'-monogallate mixture (TF-2), and theaflavin-3,3'-digallate (TF-3) are the major black tea polyphenols. Here we compared the effects of these polyphenols on cell growth, apoptosis, and gene expression in normal and cancerous cells. We showed that TF-2 (10-50 microM) inhibited the growth of SV40 transformed WI38 human cells (WI38VA) and Caco-2 colon cancer cells but had little effect on the growth of their normal counterparts. The IC50s of TF-2 for the growth inhibition of WI38 and WI38VA cells were, respectively, 300 and 3 microM. The other two black tea polyphenols, TF-1 and TF-3, did not exhibit such differential growth-inhibitory effect. TF-2, but not TF-1 or TF-3, induced apoptosis in transformed WI38VA cells but not in normal WI38 cells, suggesting that apoptosis was responsible, at least in part, for the differential growth-inhibitory effect of TF-2. Cox-2 has been implicated in intestinal carcinogenesis. Among the tea polyphenols tested, TF-2 and, to a lesser degree, (-)-epigallocatechin gallate inhibited cyclooxygenase (Cox)-2 gene expression. TF-2 at 50 microM completely blocked the serum-induced Cox-2 gene expression at both mRNA and protein level. Other genes, including c-fos, c-myc, thymidine kinase, proliferating cell nuclear antigen, BRCA1, BRCA2, and Cox-1, were not significantly affected by TF-2. These findings suggest that TF-2 may be responsible, at least in part, for the chemopreventive activity in black tea extracts.
 ...
PMID:Differential effects of theaflavin monogallates on cell growth, apoptosis, and Cox-2 gene expression in cancerous versus normal cells. 1110 14

Loss or lowered expression of BRCA1 in non-familial breast cancer has been shown in several recent studies. Understanding how BRCA1 expression is regulated should provide new insights into the role of BRCA1 in sporadic breast cancer. We have recently identified a critical 18-base pair (bp) DNA element within the minimal BRCA1 promoter whereupon the formation of a specific protein-DNA complex and transcription of BRCA1 is dependent. We now report a non tissue-specific transcriptional repressor activity, located more than 500 bp into the first intron of BRCA1. Progressive deletions from the 3'-end of intron 1 and reporter gene assays localized the repressor activity to an 83-bp region. Electrophoretic mobility shift assays with this 83 bp DNA and various sub-fragments of it showed binding of nuclear proteins to a 36 bp BstNI-BseRI fragment. Functional transcriptional repression by this 36 bp DNA could be conferred on a heterologous thymidine kinase promoter. Analysis of multiple reporter gene constructs containing the BRCA1 genomic region driving transcription in both directions suggests that the putative negative regulatory element functions to block transcription only in the BRCA1 direction, although the promoter is shared by the divergently transcribed NBR2 gene.
 ...
PMID:Identification of a novel transcriptional repressor element located in the first intron of the human BRCA1 gene. 1131 75

In contrast to hundreds of mutations found in familial breast and/or ovarian cancers, somatic mutations of BRCA1 are very rare. However, a high percentage of sporadic breast and ovarian cancers show a reduction in BRCA1 expression, suggesting that defects in transcriptional regulation is a contributing factor. BRCA1 shares a promoter with its neighboring gene, NBR2, which is transcribed in the opposite direction. We have previously shown that the transcription of BRCA1 is negatively regulated by protein factors that interact with a 36-bp segment, located 575 bp into its first intron. We now report the localization of an 18-bp transcriptional repressor element for NBR2, which resides 948 bp into its first intron. The binding of nuclear proteins to this repressor element was detected by electrophoretic mobility shift assays (EMSAs), and it conferred an orientation-dependent functional suppression onto a heterologous thymidine kinase promoter. Combined with our previous studies, a model of transcriptional regulation of the closely aligned BRCA1-NBR2 bi-directional unit is proposed. A minimal 56-bp DNA region is functional in driving transcription in both directions, while uni-directional control is provided by distinct repressors that bind to sequences located in the first intron of the respective genes.
 ...
PMID:Model of transcriptional regulation of the BRCA1-NBR2 bi-directional transcriptional unit. 1577 33

Gene therapy is a newly hatched field of biomedical research aimed at introducing therapeutically important genes into somatic cells of patients for the treatment of human disease. Whereas for inborn errors of metabolism transfer of a single gene can correct the disorder, cancer is a complex disease involving mutations in a number of protooncogenes and tumor suppressor genes as well as an imbalance and disarray in phosphorylation events and regulatory circuits of the cell cycle; transfer of the wild-type p53 or p21 tumor suppressor genes is a successful gene therapy approach leading to apoptotic death of cancer cells or in restrain of their chaotic growth. A different promising approach is transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene (suicide gene) and systemic treatment with the prodrug ganciclovir which is converted by HSV-tk into a toxic drug killing dividing cells. Expression of suicide genes, p53, and other therapeutic genes preferentially in cancer cells can be achieved by regulatory elements from tumor-specific genes such as carcinoembryonic antigen, BRCA1, and PSA.
 ...
PMID:Cancer gene therapy and immunotherapy (review). 2154

Breast cancer is the most prevalent cancer in women worldwide and is classified into ductal and lobular carcinoma. Breast cancer as well as lobular carcinoma is associated with various risk factors such as gender, age, female hormone exposure, ethnicity, family history and genetic risk factor-associated genes. Genes associated with a high risk of developing breast cancer include BRCA1, BRCA2, p53, PTEN, CHEK2 and ATM. Surgery, chemotherapy, radiotherapy and hormone therapy are used to treat breast cancer but these therapies, except for surgery, have many side-effects such as alopecia, anesthesia, diarrhea and arthralgia. Gene-directed enzyme/prodrug therapy (GEPT) or suicide gene therapy, may improve the therapeutic efficacy of conventional cancer radiotherapy and chemotherapy without side-effects. GEPT most often involves the use of a viral vector to deliver a gene not found in mammalian cells and that produces enzymes which can convert a relatively non-toxic prodrug into a toxic agent. Examples of these systems include cytosine deaminase/5-fluorocytosine (CD/5-FC), carboxyl esterase/irinotecan (CE/CPT-11), and thymidine kinase/ganciclovir (TK/GCV). Recently, therapies based on genetically engineered stem cells (GESTECs) using a GEPT system have received a great deal of attention for their clinical and therapeutic potential to treat breast cancer. In this review, we discuss the potential of GESTECs via tumor tropism effects and therapeutic efficacy against several different types of cancer cells. GESTECs represent a useful tool for treating breast cancer without inducing injuries associated with conventional therapeutic modalities.
 ...
PMID:Therapeutic potential of stem cells expressing suicide genes that selectively target human breast cancer cells: evidence that they exert tumoricidal effects via tumor tropism (review). 2273 97

Previous studies indicated that BRCA haploinsufficiency was associated with activation of the EGF receptor (EGFR) signaling pathway and increased proliferative activity in mammary epithelial cells of healthy women. We hypothesized that these processes might be reflected in the expression of serologic soluble EGFR (sEGFR) and thymidine kinase 1 (TK1) activity, which signal the initial and final steps of the proliferative pathway, respectively. We found that healthy carriers of BRCA1/2 mutations (n = 80) showed a significantly higher TK1 activity than age-matched controls (P = 0.0003), and TK1 activity was similar in women with BRCA1 and BRCA2 mutations (P = 0.74). The sEGFR concentration was significantly higher in women with BRCA1 than in controls and BRCA2 mutation (P = 0.013 and 0.002, respectively). During follow-up, four of 80 BRCA1/2 mutation carriers developed breast cancer. These women showed a significantly higher TK1 activity and somewhat higher sEGFR concentrations than the other 76 BRCA1/2 carriers (P = 0.04 and 0.09, respectively). All tumors were negative for ovarian hormone receptors, but showed a high EGFR expression. This study was limited by the short-term follow-up (mean, 27 months; range, 5-45), which resulted in a small sample size. Women with BRCA1 and BRCA2 mutations that had undergone risk-reducing bilateral salpingo-oophorectomy (BSO) showed significantly lower sEGFR compared with those without surgery (P = 0.007 and 0.038, respectively). Larger, prospective studies are warranted to investigate whether TK1 and sEGFR measurements may be useful for identifying healthy BRCA1/2 carriers with high risk of developing breast cancer; moreover, sEGFR measurements may serve as effective tools for assessing risk before and after BSO.
 ...
PMID:Increased proliferative background in healthy women with BRCA1/2 haploinsufficiency is associated with high risk for breast cancer. 2396 79

By employing the attractive performance of fluorescent carbon dots and the assistant of hairpin structure, an innovative dual-channel biosensor on the basis of gold nanoparticles (AuNPs) for detecting multiple nucleotide sequences has been successfully proposed. In brief, the fluorescence of carbon dots (CDs) was quenched in the absence of the targets, and the hairpin structure was hybridized with the AuNPs-DNA and resulted in recovering the fluorescence. Instead, the presence of breast cancer (BRCA1) RNA/DNA could specifically bind with its contrary sequence to release the CDs from AuNPs, hence leading to the fluorescence recovery as a positive signal. Again, the hairpin structure can be released in the presence of thymidine kinase (TK1) RNA/DNA, thus induced a fluorescence quenching accordingly. Subsequently, the prepared sensing model was applied to detect BRCA1 RNA/DNA respectively accompanied with a linear range of 4-120nM as well as a detection limit of 1.5nM and 2.1nM, and 10-120nM as well as a detection limit of 3.6nM and 4.5nM for TK1 RNA/DNA respectively. More importantly, this sensing model could assay any possible gene sequence or aptamer-substrate complexes by appropriately programming.
 ...
PMID:Dual-channel sensing strategy based on gold nanoparticles cooperating with carbon dots and hairpin structure for assaying RNA and DNA. 2884 82