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 murine B-cell hybridoma B9 requires interleukin-6 (IL-6) for its survival and proliferation in vitro. We show here that withdrawal of IL-6 from B9 cultures results in programmed death, concomitant with arrest of the cells in the G1 phase of the cell cycle. Unlike several other systems that undergo programmed cell death, no induction of transcripts corresponding to the testosterone-repressed message-2 or transglutaminase genes is observed during this process. Upon readdition of IL-6 to G1-arrested B9 cells, viability is maintained and entry into S phase occurs after a lag period of 10 to 12 hr. Northern blot analysis showed that the immediate-early mRNAs normally induced shortly after growth factor stimulation in quiescent fibroblasts (c-fos, c-jun, Egr-1, c-myc, JE, and KC), and other growth-related genes (2F1, c-Ha-ras, and p53), are either not induced or remain unchanged during G1 to S phase progression. A correlation was found, however, between the temporal pattern of expression of several G1/S phase genes (dihydrofolate reductase, thymidine kinase, transferrin receptor, and histone H3) and DNA synthesis. These results demonstrate that IL-6-induced viability and growth of hybridoma (and, presumably, plasmacytoma) cells is mediated via novel signal transduction pathways.
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PMID:Suppression of programmed death and G1 arrest in B-cell hybridomas by interleukin-6 is not accompanied by altered expression of immediate early response genes. 170 72

A panel of 73 samples, including 52 primary breast carcinomas, 10 normal breast tissues and 11 axillary lymph nodes, has been analysed for the presence of amplifications and gross structural alterations, in the oncogenes c-erbB-2, c-erbA, c-myc, N-myc, c-mos and c-Ha-ras. The tumours were also classified, graded and staged histopathologically and their DNA ploidy (42 samples) was determined by flow cytometry. Three breast cancer cell lines (MCF7, ZR-75-1 and T47D) were also included in the study. Amplification of c-erbB-2 was detected in 28% of the tumours, of which 91% had an increased steady-state level of c-erbB-2 mRNA. Amplification of c-erbA was found in 23% of tumours and was always associated with the amplification of c-erbB-2. Ten out of 12 (83%) tumours which had c-erbB-2 and c-erbA co-amplification had metastasised to axillary lymph nodes (P less than 0.006). However, the human thymidine kinase gene, which is present at the same chromosomal location as these two oncogenes (17q21-22), was amplified in only tw tumours. Amplification of c-myc was detected in 21% of the tumours studied, of which 82% (P less than 0.005) were of histopathological grade 3 and none were of grade 1. Flow cytometry showed that 90% (P less than 0.01) of the analysed tumours with c-erbB-2 and c-erbA co-amplification, and 70% (P less than 0.1) of those with c-myc amplification were DNA aneuploid. This study demonstrates the potential value of c-myc amplification in the assessment of the tumour grade, rather than metastatic potential; and of the co-amplification of c-erbB-2 and c-erbA as a strong indicator of metastatic potential, rather than tumour grade.
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PMID:c-erbB-2/c-erbA co-amplification indicative of lymph node metastasis, and c-myc amplification of high tumour grade, in human breast carcinoma. 257 68

Rat2 cells are thymidine kinase-deficient derivatives from the immortalized rat embryo cell line Rat1. They show no phenotypic correlates of malignancy in vitro and produce tumors in syngeneic Fischer rats after long latency periods. We have investigated how transfection with oncogenes would alter the in vitro and in vivo behavior of Rat2 cells. Thus we have manipulated Rat2 cultures in various ways. The cell lines obtained were categorized as parental, in vitro subclones, untransfected in vivo derivatives, non-oncogene (neor and tk) transfectants, oncogene (mutated c-Ha-ras, polyoma middle-T, FBR v-gag-fos-fox) transfectants, and in vivo derivatives of transfectants. They were tested in vitro for morphotype, colony formation in soft agar, growth in organ culture, invasion in organ culture, and in vivo for latency period of tumor formation, tumor growth rate, invasiveness, and metastasis. Differences between the consequences of various manipulations were found in the number of malignancy-related phenotypic alterations. The following trend could be deduced from our data: induction of invasiveness in organ culture by all manipulations; morphotypic transformation and shortening of tumor-latency period by all oncogene transfections and by passage with tumor formation in vivo; growth in organ culture and increased tumor growth rate in vivo by transfection with ras-, or fos-oncogenes and by passage in vivo. Metastatic capability (present in parental Rat2 cell tumors) and colony formation in soft agar (absent in Rat2 cells) were not affected by the present manipulations. We concluded that differences between the oncogene-transfectants and the untransfected in vivo derivatives do not lie in the expression of malignancy-related phenotypes but in the time needed to acquire them.
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PMID:Effect of oncogene transfection or passage in vivo on malignant phenotypes of rat2 cells. 269 82

To understand the mechanisms of oncogenesis by human T-cell leukemia virus type I, we have investigated the ability of the tax1, protein to modulate transcription of protooncogenes. By using a transient cotransfection assay, we report that the protooncogene fos promoter is transactivated by tax1 in a variety of cell types. Two regions containing upstream sequences between positions -362/-324 and -323/-276 of the c-fos promoter responded to this activation and also conferred tax1 responsiveness to the heterologous herpesvirus thymidine kinase promoter. These two sequences include elements mediating the induction by v-sis-conditioned medium and serum, phorbol ester, or epidermal growth factor, respectively. Furthermore, expression of the endogenous c-fos gene was activated by tax1 in human T-cell leukemia virus type I-infected cell lines. In contrast, no trans-activation of the c-myc or c-Ha-ras promoter was observed.
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PMID:c-fos promoter trans-activation by the tax1 protein of human T-cell leukemia virus type I. 284 64

The length of the prereplicative period after stimulation of quiescent WI-38 cells is prolonged in proportion to the length of time the cells are incubated prior to serum addition. Previous results from this laboratory have shown that this prolongation does not result from a delay in the induction of events which occur during the G0/G1 transition (i.e. c-fos or c-myc expression) (Owen, T., Cosenza, S., Soprano, D. R., and Soprano, K. J. (1987) J. Biol. Chem. 262 15111-15117). It was the goal of the present studies to examine the expression of other growth-associated genes known to be induced and maximally accumulate later in G1 to identify genes whose expression is coupled to entry into S rather than mitogenic stimulation. In order to do this, the temporal pattern of expression of a variety of growth-associated genes (thymidine kinase, p53, 2A9/calcyclin, ornithine decarboxylase, 4F1/vimentin, and c-Ha-ras) was studied in WI-38 cells stimulated either 12 days or 26 days after plating. We report that the time of induction and maximum accumulation of each of these transcripts, with the exception of c-Ha-ras, was delayed in the 26-day cell group for 10 h, a period of time approximately equal to the length of delay in entry of these cells into S. Thus the expression of these particular genes would appear to be closely coupled in time and sequence to the entry of cells into S. These results suggest that the prolongation of the prereplicative period in WI-38 cells is located in early G1, following the events leading to c-fos and c-myc induction but prior to the induction and maximum accumulation later in G1 of other growth-associated genes such as ornithine decarboxylase and 4F1/vimentin. In addition, these results provide molecular evidence for a definitive programmed order of gene expression during the progression of cells out of G0 through G1 to S.
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PMID:Evidence that the time of entry into S is determined by events occurring in early G1. 313 30

Restriction endonuclease analysis was used to determine the methylation status of collagen, c-Ha-ras, and thymidine kinase genes in human fibroblasts and tumor cell lines. When digested with the methylation sensitive enzymes HpaII or HhaI, the DNA of each cell line generated a unique banding pattern for each gene examined. No generalized trend of gene hypomethylation or decreases in overall cytosine methylation were observed in tumor cell lines when compared to fibroblasts. Collagen biosynthetic profiles were also determined, and no correlations could be made between patterns of type I and type III collagen gene methylation and expression. Our findings support those of a previous report in which methylation and expression of the chick alpha 2(I) collagen gene were examined, and this represents the first such analysis of the pro-alpha 1 (III) collagen gene. MspI restriction fragment length polymorphisms were detected within c-Ha-ras, pro-alpha 2(I) collagen, pro-alpha 1(III) collagen, and thymidine kinase genes. The ras gene polymorphisms can be attributed to variation in the number of tandem repeats within a MspI fragment at the 3' end of the gene. The other gene polymorphisms may be due to base pair mutations at methylated cytosine residues within CCGG sequences.
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PMID:Patterns of DNA methylation and gene expression in human tumor cell lines. 369 18

The rodent established cell lines LTk- and NIH 3T3 have been used as recipients in gene transfer experiments to study the effect of interferon treatment on the genetic and oncogenic transformation by several genes of viral and cellular origin. Our results show that interferon severely inhibits, to a similar extent, the stable transformation of Ltk- and NIH 3T3 cells by the chicken thymidine kinase (tk) gene, Ecogpt gene, simian virus 40, v-Ha-ras, and human c-Ha-ras and c-Ki-ras oncogenes. These results are consistent with an inhibition by interferon at the level of stabilization or integration, or both, of exogenous DNA sequences in the recipient cells, with an apparent effect on gene expression.
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PMID:Inhibitory effect of interferon on the genetic and oncogenic transformation by viral and cellular genes. 397 79

The hallmark of cellular aging is the failure of senescent diploid cells to enter or to complete the S phase of the cell cycle. The cause for such failure may hold the key for our understanding of the molecular basis of cellular aging. We have previously shown that aging of IMR-90 human diploid fibroblasts in culture is accompanied by a five to sevenfold decrease in both thymidine kinase activity and thymidine kinase mRNA level (Chang and Chen, 1988, J. Biol. Chem., 263:11431-11435). To examine whether attenuation of gene expression at G1/S boundary is unique for thymidine kinase or it may involve most, if not all, of other G1/S genes, we compared the expressions of two classes of G1/S genes in young and in old IMR-90 cells following serum stimulation. We found that the expression of all these genes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), ribonucleotide reductase (PNR), proliferating cell nuclear antigen (PCNA), histone H1, histone H2A + 2B, histone H3, and histone H4, was induced to high levels in young IMR-90 cells but not in old IMR-90 cells. The mRNA levels of all G1/S genes in young cells were more than tenfold higher than that in old cells 12 hr after serum stimulation. The enzymes encoded by TS and DHFR genes and dUTPase also exhibited similar age-dependent attenuation in activities. In contrast, expression of growth-related genes such as eIF-5A, c-Ha-ras, and beta-actin did not show significant differences between young and old cells after serum stimulation. Computer analysis of the promoter region of these G1/S genes revealed an Sp-1 binding site as the most common cis-element. Taken together, our results suggest that the suppression of G1/S gene expressions during senescence may be a global phenomenon and that G1/S genes may be coordinately controlled.
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PMID:Global change of gene expression at late G1/S boundary may occur in human IMR-90 diploid fibroblasts during senescence. 807 91

We have shown previously that overexpression of c-Ha-ras, v-mos or c-fos increases the spontaneous level of chromosomal aberrations and gene mutations in NIH 3T3 cells, and that reduction of the Fos protein level inhibits aberration induction by c-Ha-ras and v-mos and also by irradiation with ultraviolet light (van den Berg et al., Mol. Carcinogenesis, 4, 460-466). In order to examine whether fos is also involved in DNA recombination, thymidine kinase (tk) deficient human osteosarcoma cells containing two versions of the herpes simplex virus tk gene inactivated by base insertion were either transiently or stably transfected with various fos expression plasmids. The frequency of tk+ revertants was significantly enhanced both upon transient transfection with RSV-promoter-fos gene constructs and by stimulation of Fos synthesis in stably transfected cells harbouring an inducible metallothionein promoter-fos construct. No such increases were observed in cells transfected with plasmids containing a truncated version of c-fos. The data indicate that c-fos is involved in generating various types of genetic changes including homologous recombination; a role of c-fos in genetic instability may contribute to its action in tumor promotion and progression.
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PMID:Overexpression of c-fos increases recombination frequency in human osteosarcoma cells. 809 16