Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.28 (chloramphenicol acetyltransferase)
 5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proliferation of LNCaP 104-S cells, a clonal subline of the human prostate cancer cell line, was very slow in androgen-depleted medium but increased 10-13-fold in the presence of 0.1 nM of a synthetic androgen, R1881. This induction of proliferation was diminished at higher concentrations of R1881, indicating the biphasic nature of the androgen effect. After 20-30 passages in androgen-depleted medium, these cells progressed to 104-I cells, which exhibited much lower proliferative sensitivity to 0.1 nM R1881. After another 20-30 passages, LNCaP 104-I cells gave rise to 104-R cells, which proliferated rapidly without additional androgen. Proliferation of 104-R cells was induced 2-fold by 0.01 nM R1881 but was repressed by 0.1 nM R1881 and above. Thus, androgen induction and repression of proliferation could be seen at lower concentrations of androgen as the cells progressed. During the transition of 104-S cells to 104-R cells, the androgen receptor mRNA level increased 2.5-fold whereas the androgen receptor protein level increased 15-fold in the absence of androgen. Androgen receptor transcriptional activity, measured by androgen induction of prostate-specific antigen mRNA and chloramphenicol acetyltransferase activity in transfected cells, increased up to 20-fold during the progression. LNCaP cells, therefore, appear to be able to adapt to reduced androgen availability by increasing their sensitivity to androgen, raising questions concerning the therapeutic strategies used against prostate cancer. Androgen induction of c-myc expression in 104-R cells occurred at a 10-fold lower concentration (0.01 nM) than in 104-S cells (0.1 nM). In all stages, cell proliferation and c-myc expression were repressed by androgen at a high concentration (20 nM), but the repression of cell proliferation was blocked by retroviral overexpression of c-myc.
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PMID:Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. 751 Oct 45

Androgen receptor (AR) plays a key role in cell growth both in the normal prostate and in prostate cancer. Androgen ablation and prolonged antiandrogen therapy can give rise to AR-dependent prostate tumors, which nonetheless can grow in the androgen-deprived milieu. Here we describe the ribozyme approach to selectively degrading the AR mRNA and thereby inhibiting AR function. A trans-acting hammerhead ribozyme was designed to cleave the rat AR mRNA at the position +1827/ 1828, a region predicted to be minimally involved in generating stable secondary structures. Using AR mRNA fragments as substrates, it was established that this ribozyme can specifically cleave the RNA target in a sequence-specific manner. Kinetic experiments determined a Km for the substrate of 77 nM and a kcat/Km value of 1.8 x 10(7) M(-1) x min(-1), suggesting a catalytic efficiency similar to that of protein enzymes such as the relatively nonspecific ribonuclease A and a sequence-specific endonuclease EcoRI. Transient cotransfections of prostate-derived PC3 cells with three plasmids, an AR-inducible chloramphenicol acetyltransferase (CAT) reporter, an AR expression vector, and a ribozyme expression vector, showed that the ribozyme was capable of reducing the functional activity of AR. At an equimolar ratio of the AR expression plasmid to ribozyme expression plasmid, androgen-inducible CAT activity was inhibited 70%. Similar extents of inhibition were also observed at the cellular mRNA level using ribonuclease protection assays, indicating that the ribozyme functioned as an AR mRNA cleaving enzyme in cellulo. Immunocytochemical examination revealed a decline of AR immunoreactivity in ribozyme-transfected cells. In addition, no morphologically detectable cellular abnormalities were associated with ribozyme expression, indicating the absence of deleterious side effects. These results offer a new avenue for the control of AR function and cell growth, especially in the case of androgen-resistant, but AR-dependent, prostate cancer cells.
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PMID:Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme. 977 79