Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Tri4 gene of Fusarium sporotrichioides was isolated from a cloned DNA fragment carrying the Tri5 gene by complementation of a Tri4- mutant. The nucleotide sequence of Tri4 was determined and the locations of three introns were identified. Analysis of Tri4 mRNA levels revealed that transcription reached maximum levels coincidently with the onset of trichothecene biosynthesis, and then declined 20-fold over the next 8 h. Disruption of Tri4 resulted in the loss of production of both trichothecenes and apotrichodiol and the accumulation of the unoxygenated pathway intermediate trichodiene. Transformants lacking a functional Tri4 gene were able to convert isotrichotriol, an early pathway intermediate, to T-2 toxin suggesting that most pathway enzymes are present in Tri4- mutants. These data suggest that the enzyme encoded by Tri4 catalyzes the first oxygenation step in the trichothecene pathway and participates in apotrichodiol biosynthesis. Tri4 encodes a protein of 520 residues (M(r) = 59 056) that shows significant homology with members of the superfamily of cytochromes P450. It appears most similar to the CYP3A subfamily (24.6% amino acid identity). Because it contains less than 40% positional identity with other cytochromes P450, the Tri4 gene has been placed in a new cytochrome P450 gene family designated CY P58.
Mol Gen Genet 1995 Jul 22
PMID:The Tri4 gene of Fusarium sporotrichioides encodes a cytochrome P450 monooxygenase involved in trichothecene biosynthesis. 765 33

In the rat liver, cytochrome P450 catalyzes the hydroxylation of steroid hormones. The expression and activity of some P450 isozymes are regulated by sex steroid hormones. Steroid 21-hydroxylase activity in rat liver is provided mainly by CYP2C6. We studied the regulation of 21-hydroxylase activity by sex steroid hormones in rat primary hepatocyte culture. We added estrogens (estrone, estradiol, estriol) and androgens (testosterone, dihydrotestosterone), (ranging from 10(-9) to 10(-5)M) to the culture. The 21-hydroxylase activity was stimulated by estrogens and was suppressed slightly by androgen in a dose-related manner. The results of our studies demonstrated that sex steroid hormones act differently on 21-hydroxylase activity in rat hepatocytes and, thus, support the hypothesis that the extra-adrenal production of deoxycorticosterone from circulating progesterone is increased during pregnancy by the massive presence of estrogens.
J Steroid Biochem Mol Biol 1995 Aug
PMID:Dual regulation of 21-hydroxylase activity by sex steroid hormones in rat hepatocytes. 766 90

Aromatase P450 (P450arom) is the enzyme responsible for estrogen biosynthesis. Studies of the relationship of the function of this enzyme to its structure have been hampered by lack of a suitable preparation. In the present report we describe the expression of a recombinant derivative of P450arom in insect cells by means of the baculovirus vector system. This protein, which lacks the first 41 amino acids from the N-terminus, and hence the membrane-spanning region, has spectral properties and activity similar to that of the wildtype protein. Moreover, the presence of a hexameric histidine tag at the C-terminus permits its facile purification by means of nickel-agarose affinity chromatography. This system permits the synthesis of quantities of a biologically active derivative of P450arom suitable for studies designed to explore the relationship of function to structure.
Mol Cell Endocrinol 1995 Apr 01
PMID:Expression of a recombinant derivative of human aromatase P450 in insect cells utilizing the baculovirus vector system. 766 73

The aim of this study was to evaluate the occurrence and physiological consequences of apoptosis in primary cultures of bovine adrenocortical cells (of fasciculata-reticularis origin). Under ACTH-free culture conditions, we observed apoptotic cells in the cell layer and the accumulation of apoptotic bodies in the culture medium. These were hardly detectable in ACTH-supplemented cultures. Under ACTH-free conditions, the DNA content of apoptotic bodies collected over 48 h represented up to 10-15% of that of the cell layer at the onset of the culture (as compared to 3% in ACTH-supplemented cultures). Past the fourth day of culture in the absence of ACTh, most cells lacked several markers of their originating fasciculata-reticularis phenotype and progressively evolved to an undifferentiated phenotype. The vast majority of the apoptotic bodies released during the first 4 days of culture were immunoreactive for P450 17 alpha. Inversely, during the same period of time, the proliferating cells (PCNA-positive) did not appear to express P450 17 alpha. Therefore, apoptosis could contribute, together with dedifferentiation, to the phenotype shift observed in ACTH-depleted cultures of adrenal fasciculata-reticularis cells. These observations also characterize this endocrine cell system as an in vitro model for the study of hormone-repressed apoptosis.
Mol Cell Endocrinol 1995 Apr 28
PMID:Contribution of apoptosis to the phenotypic changes of adrenocortical cells in primary culture. 767 47

Benign prostatic hyperplasia (BPH) is the most common neoplastic growth in men and is the most frequent cause of urinary flow obstruction at the bladder neck. In addition to the clear evidence in favor of the androgen dependency of BPH, the involvement of the stroma, stromal-epithelial interaction and the role of estrogens have gained much interest in connection with the pathogenesis of this disease. For this reason, specific aromatase inhibitors such as atamestane (1-methyl-1,4-androstadiene-3,17-dione) have recently attracted attention due to their potential use in the treatment of BPH. The pharmacological action of atamestane as a new competitive and irreversible inhibitor of estrogen biosynthesis has been evaluated in mice, rats, rabbits, dogs, monkeys and in man. In all species tested so far, atamestane lacks other intrinsic hormonal or antihormonal activities and shows no inhibition of other cytochrome-P450 dependent enzymes of adrenal steroidogenesis. However, it inhibits the estrogen-related negative feed-back. The extent and consequence of the induced counter-regulation of the pituitary-hypothalamic axis show major sex- and species-specific differences. In BPH animal models, atamestane is highly effective in inhibiting estrogen-induced hyperplastic changes in the fibromuscular stroma of the prostate in androstenedione-treated dogs and monkeys. In male volunteers and BPH patients, atamestane induces an expected dose-dependent reduction of serum estrogen concentrations with slight increases in androgen level. In conclusion, all available results indicate that atamestane is a selective (no inhibition of adrenal function), pure (= specific--no endocrine side-effects) and highly effective steroidal aromatase inhibitor with excellent safety profile. Based on our preliminary results aromatase inhibitors seem to be promising compounds for the treatment of BPH.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Atamestane: an aromatase inhibitor for the treatment of benign prostatic hyperplasia. A short review. 768 38

The role of protein kinase C (PKC) in the regulation of basal steroidogenesis and steroid hydroxylase gene expression in Y1 adrenocortical cells was investigated. Treatment of Y1 cells with either staurosporine or calphostin C, inhibitors of PKC, increases steroid hormone production up to 7-fold. Induction of P450-cholesterol side chain cleavage enzyme (SCC) mRNA expression parallels induction of steroidogenesis by the PKC inhibitors. Staurosporine increases expression of a transiently transfected SCC promoter--human growth hormone construct in Y1 cells, indicating that PKC regulates expression of SCC mRNA at the level of transcription. Treatment with staurosporine increases expression of mRNA for two additional steroid synthetic enzymes, P450-11 beta-hydroxylase and 3 beta-hydroxysteroid dehydrogenase. These data indicate that PKC acts as a tonic negative regulator of basal steroidogenesis in Y1 cells by suppressing expression of mRNA encoding the steroid synthetic enzymes. Protein kinase A (PKA) and PKC have reciprocal effects on steroidogenesis and expression of the steroid synthetic enzymes in Y1 cells. However, the results of this study demonstrate that these signaling pathways are not interdependent. Steroid production by Y1 cells treated with (Bu)2cAMP and calphostin C together is equal to the sum of steroid production after treatment with either agent alone. Pretreatment of Y1 cells with Rp-8-Bromo-cAMP, a specific inhibitor of PKA, prevents induction of steroidogenesis by (Bu)2cAMP, but not by staurosporine, indicating that PKC is not dependent on PKA activity. In addition, induction of SCC mRNA expression by staurosporine, in Y1 cells which are defective in activation of PKA (Y1 kin-8), is equivalent to induction in Y1 cells. These data indicate that PKA and PKC regulate basal steroidogenesis through independent effects on expression of the steroid synthetic enzymes.
Mol Endocrinol 1993 Aug
PMID:Protein kinase C is a tonic negative regulator of steroidogenesis and steroid hydroxylase gene expression in Y1 adrenal cells and functions independently of protein kinase A. 769 83

Four cDNA clones were isolated from a porcine adrenal gland library by using a bovine cytochrome P450(11 beta) cDNA fragment as a probe. Nucleotide sequences of the four clones overlapped with each other. The deduced amino acid sequences indicated that these clones were derived from a porcine P450(11 beta) cDNA. Consecutive alignment of these clones covered almost 70% of a coding region of the cDNA, but its 5'-terminus was missing. The adrenal mRNA was reverse-transcribed, and polymerase chain reaction was used to obtain a cDNA fragment including the 5'-terminus. A cDNA constructed from this fragment and the isolated four fragments covered the entire apparent open reading frame of the enzyme, which was thus concluded to comprise 503 amino acids including a putative extension peptide of 24 amino acids at the NH2-terminus. The amino acid sequence was 82% identical to that of bovine P450(11 beta)-3. The cDNA was transfected into COS-7 cells, and steroidogenic activity of the cells was measured. The cells not only converted 11-deoxycorticosterone to corticosterone and 18-hydroxycorticosterone, but also produced aldosterone. Thus we conclude that the primary sequence of porcine P450(11 beta) which plays a role in the biosynthesis of glucocorticoids as well as mineralocorticoids was determined.
J Steroid Biochem Mol Biol 1995 Mar
PMID:Cloning and expression of cytochrome P450(11 beta) of porcine adrenal cortex. 769 43

The evidence was presented that steroid hydroxylating enzyme complex induced by substrate in the filamentous fungus Rhizopus nigricans (R. nigricans) alleviated toxic effect(s) of the steroid on fungal growth. The growth inhibition of fungal mycelium observed in steroid-containing culture(s) became much more obvious when fungal mycelia were grown in the simultaneous presence of inducing steroid and the P450(11 alpha) inhibitor metyrapone. On the other hand, in experiments where we followed the fate of radioactively labelled progesterone added to the mycelial suspension, we noticed that steroid, after being initially accumulated in the microorganism, was, after some time, released from it; the latter phenomenon was not observed if induction of 11 alpha-hydroxylase was prevented by cycloheximide. Results of experiments presented in this communication can be regarded as the first strong indication that the biological role of P450(11 alpha) induction in R. nigricans is in removal of steroids which are toxic for the mycelium.
J Steroid Biochem Mol Biol 1995 Mar
PMID:The role of cytochrome P450(11 alpha) in detoxification of steroids in the filamentous fungus Rhizopus nigricans. 769 48

Cytochromes P450 (P450s) are inducible drug-metabolizing enzymes involved in the metabolism of numerous endogenous and exogenous substrates. The regulation of some of these enzymes during experimental diabetes has been reported, but the direct involvement of insulin and the mechanism of its action remain unclear. The aim of our work was to study the effects of insulin on P450 2B and 2E expression in differentiated Fao hepatoma cells. Exposure of the cells to 0.1 microM insulin caused 60% and 80% decreases in the steady state levels of P450 2B and 2E proteins, respectively, within 24 hr. Before this, a rapid decrease in the corresponding messages was observed. Indeed, 5-6 hr of insulin treatment produced 80 and 50% decreases in P450 2B and 2E mRNA levels, respectively. Nuclear run-on transcription and mRNA turnover studies were performed to determine the mechanism (transcriptional and/or post-transcriptional) by which insulin modulated these mRNA levels. From our results, it can be concluded that insulin down-regulates the expression of P450 2B by shortening the half-life of its mRNA (half-lives of 6.9 hr without insulin and 3.6 hr with insulin), whereas it down-regulates the expression of P450 2E both by weak repression of the transcription rate (-30%) and, in particular, by acceleration of its mRNA turnover (half-lives of 8.5 hr without insulin and 3.3 hr with insulin).
Mol Pharmacol 1995 Mar
PMID:Insulin down-regulates cytochrome P450 2B and 2E expression at the post-transcriptional level in the rat hepatoma cell line. 770 Feb 45

A microsomal cytochrome P450 from the house fly (Musca domestica), termed P450lpr, is involved in P450 monooxygenase-mediated pyrethroid resistance and is expressed at 8-fold higher levels in the insecticide resistant LPR strain compared to a susceptible strain. An internal cDNA sequence was amplified by polymerase chain reaction (PCR) using degenerate primers based on known P450lpr polypeptide sequences, and the remainder of the sequence was amplified by single side-specific PCR. A 1.8 kb cDNA sequence was obtained from 3 overlapping PCR products, with an open reading frame encoding a P450 protein of 516 residues (M(r) 59,182). This gene has been designated CYP6D1 within the P450 gene superfamily. CYP6D1 exhibits most similarity (28.2-29.8% positional identity) to butterfly CYP6B1, house fly CYP6A1 and Drosophila CYP6A2, and also exhibits comparable similarity (24.7% identity) to rat CYP3A1. The deduced protein sequence contains a hydrophobic N-terminal region and conserved sequences thought to be involved in heme-binding and electron donor-protein interactions. Comparison of CYP6D1 with its four most similar proteins (CYP6B1, CYP6A1, CYP6A2 and CYP3A1) reveals the presence of extensive stretches of residues in an alignment row in 2 possible substrate-binding regions. Three introns of 74, 66 and 64 bp, having 5'-GT and AG-3' ends, split the CYP6D1 coding region in genomic DNA. Results indicate that CYP6D1 is likely the P450lpr gene.
Insect Biochem Mol Biol 1995 Feb
PMID:cDNA and deduced protein sequence of CYP6D1: the putative gene for a cytochrome P450 responsible for pyrethroid resistance in house fly. 771 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>