Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The natural hormone estradiol (E2) induces tumors in rodents and various types of DNA damage in vitro and in vivo, but has not been mutagenic in bacterial or mammalian assays. Recent reports of chromosomal and genetic lesions induced by E2 has led us to re-examine the mutation frequency and molecular alterations of the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene in Chinese hamster V79 cells. E2 at both physiological and pharmacological concentrations (10-11, 10-10, and 10-7, 10-6 M) significantly increased the mutation frequency of the hprt gene by 2. 57-, 3.45-, 2.63-, and 8.78-fold, respectively, compared to the controls, while 10-13, 10-12, 10-9, or 10-8 M E2 induced little change (< or =0.93-fold). PCR and a molecular analysis of the hprt coding sequence identified genetic lesions in the cDNA and/or genomic DNA in 15 of the 21 picked E2-induced mutants (71%). Simple base substitutions, such as Tright curved arrow G or Tright curved arrow A transversions, were the most common mutations (8/21 or 38%) and frequently occurred at 122 bp or 407 bp of the hprt coding sequence. Deletion mutations were detected in 6 of the 21 clones (29%). An Aright curved arrow G and a Cright curved arrow T transition and a four-base insertion (TATT) were identified each in one mutant clone. A RT-PCR analysis demonstrated an abundant expression of the estrogen receptor-alpha (ERalpha). However, ICI 182,780, an antagonist of ERalpha, acted in an additive manner with E2 and increased the hprt mutation frequency. In conclusion, E2 induces a low frequency of mutations (deletions and point mutations) in V79 cells, which is consistent with the weak carcinogenic activity of this hormone. The mutagenic effects of E2 in V79 cells are not mediated by the ERalpha.
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PMID:Frequency and molecular analysis of hprt mutations induced by estradiol in Chinese hamster V79 cells. 1107 99

Fibulin-1 is an extracellular matrix protein induced by estradiol in estrogen receptor (ER) positive ovarian cancer cell lines. Alternative splicing of fibulin-1 mRNA results in four different variants named A, B, C and D that may have distinct biological functions. We studied the relative expression of fibulin-1 mRNA variants and their estrogen regulation in human ovarian cancer cells. In ovarian tissues and cancer cell lines, fibulin-1C and -1D are the predominant forms, whereas fibulin-1A and -1B are weakly expressed. We developed a competitive PCR assay based on coamplification of fibulin-1C and -1D to study the relative expression of these fibulin-1 variants in human ovarian samples. In ovarian cancer cell lines and ovarian cancer samples, there was a marked increase in the fibulin-1C:1D and fibulin-1C:HPRT mRNA ratios as compared to normal ovaries. In the BG1 estrogen receptor positive ovarian cancer cell line, fibulin-1C mRNA was induced by estradiol in a dose- and time-dependent manner. Since others and we have previously shown an increased expression of ERalpha as compared to ERbeta in ovarian cancer cells, we investigated whether ERalpha or ERbeta is involved in this induction. For this aim, MDA-MB-231 breast cancer cell line, which expresses both low basal levels of ERs and fibulin-1, was infected with recombinant ERalpha or ERbeta encoding adenovirus and treated with estradiol. Fibulin-1C was induced by estradiol in ERalpha- but not ERbeta-infected cells, suggesting that fibulin-1C induction is mediated through ERalpha. In ovarian tumors, a trend towards a correlation between fibulin-1C and ERalpha expression levels was noted. In conclusion, this study showed an increased fibulin-1C:-1D mRNA ratio in ovarian cancer cells as compared to normal ovaries. This finding suggests that the C variant may be involved in ovarian carcinogenesis. Fibulin-1C overexpression may thus be a clue for the understanding of a putative role of estrogens in ERalpha promoted ovarian tumor progression.
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PMID:Estrogen induction and overexpression of fibulin-1C mRNA in ovarian cancer cells. 1185 Aug 27