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

The normal mouse mammary epithelial cells, NOG-8, respond to the mitogenic signal of prolactin with a 2.5-fold increase in cell number within 3 days in vitro. When prolactin is added to subconfluent cells for 5-15 min, there is a 5-fold increase in protein kinase C activity. Upon longer exposure (24 h) to the hormone, the enzyme activity returns to that of control. The potent protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), blocks both the prolactin-induced enzyme activity and subsequent increase in cell number. Prior to prolactin treatment, 90% of the protein kinase C activity resides in the cytosol with only 10% associated with the membranes. After only 5 min of prolactin treatment, 70% of the enzyme activity is now localized to the membranes. These data suggest that prolactin uses the protein kinase C pathway for signal transduction in NOG-8 cells thus leading to enhanced cell growth.
Mol Cell Endocrinol 1992 Dec
PMID:Prolactin-induced protein kinase C activity in a mouse mammary cell line (NOG-8). 130 98

Levonorgestrel (LNG) is a synthetic steroid that displays potent progestational and androgenic effects but it lacks estrogen-like activity. To examine the mode of action of this progestin, we studied its metabolism in vitro in target organs and the specific interactions of LNG and its metabolites with putative steroid receptors. The results demonstrated that [3H]LNG was efficiently converted to A-ring reduced derivatives when incubated with rat hypothalamus and pituitary. Under optimal incubation conditions, [3H]5 alpha-dihydro LNG (5 alpha-LNG) and [3H]3 alpha,5 alpha-tetrahydro LNG (3 alpha,5 alpha-LNG) were identified as the major metabolic conversion products, while [3H]3 beta,5 alpha-LNG formation occurred to a lesser extent. A-ring reduction of LNG was NADPH-dependent. Assessment of the relative binding affinities of LNG and its derivatives to progesterone (PR), androgen (AR) and estrogen (ER) receptors by displacement analysis revealed that unchanged LNG binds with high affinity to PR and AR but not to ER. 5 alpha-LNG exhibited a diminished though significant interaction with PR and an enhanced binding affinity for AR as compared with LNG, indicating that 5 alpha-reduction of LNG increases its affinity for AR. The most striking finding was that further reduction of the 5 alpha-LNG molecule at C-3 abolished its binding activity to PR, AR, and even to ER. The overall data provides a plausible explanation for the lack of estrogen agonistic action of LNG and for its potent progestational and androgenic effects.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Mechanism of action of levonorgestrel: in vitro metabolism and specific interactions with steroid receptors in target organs. 156 65

The whey acidic protein (WAP) is a major milk protein. It is abundantly expressed in mammary epithelial cells, and its gene is controlled by lactogenic hormones. The identification of regulatory cis-acting sequences of the mouse WAP gene was so far dependent on the analysis of transgenic animals. We report here the possibility of analyzing regulatory sequences by gene transfer experiments using the lactogenic hormone-dependent mammary epithelial cell line HC11. A WAP-chloramphenicol acetyltransferase construct containing 2.5 kilobases of the 5'-flanking sequence of the WAP gene was stably transfected into HC11 cells. High chloramphenicol acetyltransferase activity was induced in pools of transfected cells cultured in the presence of the lactogenic hormones glucocorticoid, PRL, and insulin. A lower induction was observed by glucocorticoid hormone alone. PRL by itself was not able to induce the WAP gene promoter above the level observed in the absence of lactogenic hormones. A time course of hormone induction showed a weak initial response with a steady increase over at least 4 days of hormone treatment. Induction was not observable in the mammary epithelial cell line NOG-8 and NIH3T3 fibroblasts, despite the presence of functional glucocorticoid receptor in these cells. This indicates the requirement for a cell type-specific transcription factor present in the mammary epithelial cell line HC11, but not in NOG-8 epithelial cells or NIH3T3 fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1991 Nov
PMID:Lactogenic hormone and cell type-specific control of the whey acidic protein gene promoter in transfected mouse cells. 168 65

Weight gain and psychomotor development of breastfed infants of Egyptian mothers using Norplant, Cu T-380A IUDs, norethisterone enanthate injectables (NET-EN), Depo Provera and a levonorgestrel minipill were compared in 2 trials. First, groups of 120 women using Norplant and NET-EN were compared to a control group using IUDs, beginning 5-7 weeks postpartum. There were no differences in infant weight gain, mid-arm circumference, triceps-skin-fold thickness, or timing of motor milestones. The mean growth curve of all 3 groups were close to that of the 50th percentile for Egyptian infants. While timing of initiation of supplements was similar in the 3 groups, complete weaning occurred first in the IUD group, second in the Norplant group, and last in the NET-EN users. A second trail compared progesterone implants injected with a trocar that resulted in a blood level of 3 ng/ml for 5 months, with Population Council vaginal rings releasing 10 progesterone/24 hours, and CuT-380A IUDs. Serum progesterone in the ring users averaged 5.2 ng/ml for the 1st 2 weeks, then leveled off at about 4 ng/ml for about 2 months, falling to about 3 ng/ml for the last 3 weeks of use. Each women used 4 rings per year. Evidence of ovulation by ultrasonic vaginal probe and assay of estradiol and progesterone was apparent in 25% of vaginal ring users, compared to 55.9% of controls in the 2nd 6 months postpartum. There was 1 pregnancy in a ring users. The continuation rates were 66.6% for rings and 85.5% for IUDs. The reasons for discontinuation in vaginal ring continuation were logistical problems and unfamiliarity.
J Steroid Biochem Mol Biol 1991
PMID:Contraception with progestogens and progesterone during lactation. 183 50

Ivermectin is a member of the avermectin family of compounds that are used to treat helminth and arthropod diseases in humans, domestic animals, and plants. A membrane-bound high affinity ivermectin binding site was extracted from Caenorhabditis elegans with the nonionic detergent 1-O-n-octyl-beta-D-glucopyranoside. The free-living nematode C. elegans is highly sensitive to the avermectins and was used as a model of parasitic nematodes. The membrane-bound and detergent-solubilized ivermectin binding sites are stable and exhibit high affinity binding, with dissociation constants of 0.11 nM and 0.20 nM, respectively. The maximum binding of [3H]ivermectin is 0.54 pmol/mg of membrane protein and 0.66 pmol/mg of detergent-soluble protein. Kinetic analysis of ivermectin binding shows that the ivermectin binding sites form a slowly reversible complex with ivermectin. The rates of dissociation of [3H]ivermectin with the solubilized and membrane-bound binding sites are 0.005 min-1 and 0.006 min-1, respectively. The association rate of the soluble binding site is 0.053 nM-1 min-1, slightly slower than that observed for the membrane-bound site, 0.074 nM-1 min-1. To characterize the ivermectin binding site, competition experiments were performed by inhibiting [3H]ivermectin binding with several avermectin derivatives and the neurotransmitter gamma-aminobutyric acid (GABA). The order of potency was 22,23-dihydroavermectin B1a monosaccharide greater than 22,23-dihydroavermectin B1a aglycone greater than 3,4,8,9,10,11,22,23-octahydro B1 avermectin for both the membrane-bound and NOG-soluble binding sites. GABA did not compete with ivermectin binding, although it has been suggested that ivermectin acts at the GABA-gated chloride channel in some invertebrate systems. Optimum ivermectin binding and assay conditions have been determined. The detergent-soluble ivermectin binding site appears to be negatively charged and has a pl of 4.0 and an apparent Mr in Triton X-100 micelles of 340,000. Detergent solubilization of a high affinity ivermectin binding site will enable the subsequent purification and characterization of a putative site of ivermectin action.
Mol Pharmacol 1991 Aug
PMID:Solubilization and characterization of a high affinity ivermectin binding site from Caenorhabditis elegans. 187 15

To determine whether the enhanced expression of transforming growth factor alpha (TGF alpha) is sufficient to induce the neoplastic transformation of an immortalized population of mammary epithelial cells, we cotransfected NOG-8 cells, a cloned mouse mammary epithelial cell line, with a simian virus 40-human TGF alpha cDNA expression vector plasmid and a pSV2neo plasmid. After cotransfection, nine G418-resistant NOG-8 colonies were cloned and expanded. All clones were subsequently analyzed for TGF alpha mRNA expression by northern blot analysis, TGF alpha secretion, anchorage-dependent growth in serum-free medium, anchorage-independent growth in soft agar, and tumorigenicity in nude mice. Three TGF alpha-transfected NOG-8 clones expressed high levels of a specific TGF alpha mRNA, secreted elevated levels of TGF alpha into the culture medium (177-595 ng/10(8) cells/48 h), exhibited an enhanced growth rate, grew aggressively as colonies in soft agar, and formed undifferentiated, invasive carcinomas in nude mice. A neutralizing mouse monoclonal antibody generated against the low molecular weight human TGF alpha peptide was able to inhibit colony formation in soft agar by TGF alpha-transfected NOG-8 clones that produced high levels by TGF alpha. This inhibition suggested that TGF alpha acted through an external autocrine loop. NOG-8 cells and NOG-8 cells transfected with a pSV2neo plasmid alone secreted very low levels of TGF alpha, failed to grow as colonies in soft agar and did not form tumors in nude mice. These results demonstrate that overexpression of a human TGF alpha cDNA in immortalized, nontransformed mouse mammary epithelial cells can induce a transformed phenotype in vitro and can facilitate tumor formation in vivo.
Mol Carcinog 1989
PMID:Transformation of an established mouse mammary epithelial cell line following transfection with a human transforming growth factor alpha cDNA. 278 19

NOG-8 ras cells are a normal mouse mammary epithelial cell line transfected with a plasmid containing a glucocorticoid-inducible mouse mammary tumor virus long terminal repeat linked to the activated c-Ha-ras protooncogene. After addition of dexamethasone, there is a rapid induction (within 1-3 h) of p21ras protein that is concomitant with a parallel induction of the c-Ha-ras specific mRNA. After 4-6 days of dexamethasone treatment, NOG-8 ras cells are able to grow as colonies in semisolid medium. Between 9 and 12 days of dexamethasone treatment, there is a 5- to 6-fold increase of transforming growth factor alpha (TGF alpha) activity in the conditioned medium from NOG-8 ras cells. A 60-65% reduction in epidermal growth factor cell surface receptors on NOG-8 ras cells also occurs during this time interval. A 3- to 4-fold increase of the expression of a specific TGF alpha mRNA can be detected within 2 days of dexamethasone treatment, preceding the increase in TGF alpha protein found in the conditioned medium. Exogenous TGF alpha is able to stimulate in a dose-dependent fashion the anchorage-dependent and anchorage-independent growth of NOG-8 ras cells to a level comparable to that observed in dexamethasone treated ras-transformed NOG-8 ras cells. These results suggest that the enhanced expression of TGF alpha after induction of an activated ras protooncogene may be necessary for the anchorage-independent growth and subsequent morphological changes and the enhanced growth rate observed in ras-transformed mammary epithelial cells.
Mol Endocrinol 1988 Dec
PMID:Induction of transforming growth factor alpha expression in mouse mammary epithelial cells after transformation with a point-mutated c-Ha-ras protooncogene. 306 55

Subdermal contraceptive implants deliver progestin from polymer capsules or rods placed under the skin. Diffusing slowly from the polymer containers at a stable rate, the hormone provides contraception for 1-5 years, with the period of protection conferred dependent upon the specific progestin and type of polymer employed. Once inserted, the device allows a woman to have sexual intercourse over a certain period of time without any significant risk of becoming pregnant. Protection is ensured with a low drug dosage and no estrogen, and fertility is readily reversible once the implants are removed. The levonorgestrel implant Norplant R is the only subdermal contraceptive implant system approved for distribution. Annual pregnancy rates using Norplant are extremely low. Menstrual problems are the main reason why women discontinue using Norplant. Research is ongoing to reduce the number of implanted units and to introduce other progestins which may minimize side effects. Norplant-2 was designed to release the same dose of progestin from only two covered rods. Nestorone, 3-Keto-desogestrel, and Uniplant are single implants under development which are expected to be effective for 1-2 years. Completed phase II clinical trials with Nestorone found no pregnancies in 1570 woman-months of use, although bleeding irregularities occurred in 20-30% of women. A multicenter study is ongoing with a newly-designed 3-keto-desogestrel implant named Implanon, as well as another multicenter study with Uniplant, an implant which releases nomegestrol acetate with a one-year duration of action.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Subdermal contraceptive implants. 762 59

A cell surface proteoglycan, syndecan-1, has been shown to participate in the maintenance of the epithelial cell morphology. A point mutated activated c-Ha-ras gene under the control of the glucocorticoid inducible MMTV-LTR promoter was transfected into the mouse mammary epithelial cell line, NOG-8. The NOG-8 ras cells were used to study changes in syndecan-1 expression during epithelial transformation. NOG-8 ras cells, when induced to express Ha-ras, transformed and formed foci in monolayer cultures and colonies in suspension cultures. Expression of syndecan-1 at the cell surface was markedly reduced in cells showing the transformed phenotype. The accumulation of newly synthesized core protein of syndecan-1 was suppressed in these cells, whereas mRNA levels remained unchanged. This novel finding indicates that syndecan-1 expression is translationally suppressed in the Ha-ras-transformed epithelial cells. Hence, syndecan-1 loss during epithelial transformation could take place without altering syndecan gene transcription and, on the other hand, could be one of the critical events involved in malignant transformation.
Mol Biol Cell 1993 Aug
PMID:Translational suppression of syndecan-1 expression in Ha-ras transformed mouse mammary epithelial cells. 824 70

A previous report has shown that progesterone up-regulates cathepsin D expression in human endometrial cell culture. In women using the levonorgestrel-releasing Implant Norplant, the plasma levonorgestrel and immunoreactive endometrial progesterone receptor concentrations are elevated. However, the functional status of these receptors is not known. This study used endometrial cathepsin D expression both as an indirect marker for the functional status of endometrial progesterone receptors, and to identify the cell types that express cathepsin D. The results show that cathepsin D is primarily found in glandular epithelia and luminal epithelia in control and Norplant endometria. There is no significant difference in cathepsin D expression between the control and Norplant endometria, between the various stages of the menstrual cycle, or between Norplant users with varying degrees of breakthrough bleeding. Cathepsin D is also detected in cells scattered in the stroma in both control and Norplant endometria. The majority of these cells are macrophages. These data indicate that there is no evidence for progesterone regulation of cathepsin D in the human endometrium. Cathepsin D thus cannot be used as a marker for the functional status of progesterone receptors found in the Norplant-exposed endometrium.
Mol Hum Reprod 1996 Apr
PMID:Immunohistochemical detection of cathepsin D in endometrium from long-term subdermal levonorgestrel users and during the normal menstrual cycle. 923 85


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