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)

It is still undetermined which GTP-binding (G) protein is involved in the regulation of prolactin (PRL) release and through which effector. This study shows that, when compared to normal pituitary tissue, the levels of alpha o protein were very low in dopamine (DA)-resistant, PRL-secreting pituitary tumors 7315a and MtTW15, while alpha o mRNA was present in the two tumors. In the MtTW15 tumor alpha i1, alpha i2 and alpha i3 levels were decreased while those of alpha s42 and alpha s47 were increased, and in the 7315a tumor alpha i2, alpha i3 and beta levels were decreased and those of alpha s47 increased. In an estrone-induced, DA-sensitive prolactinoma the levels of alpha i3 were greatly reduced. DA was unable to inhibit basal PRL release by 7315a and MtTW15 and basal cAMP accumulation by adenomatous and MtTW15 cells. Vasoactive intestinal peptide (VIP) increased both cAMP accumulation and PRL release by all cell preparations which could be suppressed by DA with adenomatous and 7315a but not with MtTW15 cells. These and previously published results provide circumstantial evidence that alpha o, alpha i1 and alpha i3 are all involved in the transduction of the DA inhibitory message while alpha s47 transduces cAMP activating messages and alpha s42 is responsible for the constitutive activation of L-type Ca2+ channels, adenylate cyclase and baseline PRL release.
Mol Cell Endocrinol 1991 Jun
PMID:G proteins in normal rat pituitaries and in prolactin-secreting rat pituitary tumors. 165 58

Hypophyseal portal dopamine is a major negative regulator of pituitary prolactin (PRL) production. Dopamine has been reported to repress PRL gene transcription in pituitary cells. To facilitate further study of the effect of dopamine on PRL gene activation, we introduced PRL promoter and D2 receptor (D2R) constructs into GH3 cells. Since two D2R isoforms (termed D2S and D2L) have been cloned previously, we first determined which isoform(s) is present in the lactotroph by measuring the level of each mRNA species in rat prolactinoma. mRNA for each D2R isoform was found to be present, with the D2L mRNA in great (c. 6-fold) excess. Because the lactotroph contains both isoforms, the effect of each on the PRL promoter was investigated. The cDNA for each receptor isoform was synthesized by polymerase chain reaction, and cloned into an RSV-based expression vector. GH3 cells were then transiently co-transfected with either of the resulting RSV-D2R constructs plus a PRL-chloramphenicol acetyltransferase (CAT) construct containing the first 1957 base-pairs of PRL gene 5'-flanking DNA. The cells were then incubated 48 h plus or minus the dopamine agonist ergocryptine (ECR). In the presence of either RSV-D2R isoform, ECR yielded a 4-5-fold decrease in CAT activity, an effect not seen in the absence of the RSV-D2R. The promoter specificity of this effect was demonstrated by the inability of ECR to regulate expression of a control RSV-CAT construct. The PRL promoter repression mediated by each receptor isoform had appropriate pharmacology: the specific D2R agonist, quinpirole, yielded results similar to ECR, and the ECR repression was reversed by the dopamine antagonist spiperone.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1991 Aug
PMID:Either isoform of the dopamine D2 receptor can mediate dopaminergic repression of the rat prolactin promoter. 183 94

The effects of aging in the female rat were analyzed in terms of tyrosine hydroxylase (TH) gene expression and serum prolactin levels. The number of tuberoinfundibular dopaminergic (TIDA) neurons and the concentration of TH mRNA per cell was greater in 16- to 18-month-old rats than in 25-month-old rats. The amount of TH immunostaining was more intense in the median eminence of the 18-month-old rats compared to either younger or older rats. Plasma prolactin levels were moderately elevated in 18-month-old rats compared to 4-month-old rats, and extremely elevated in 25-month-old rats due to the occurrence of pituitary prolactinomas. There were no detectable changes in TH mRNA levels in the substantia nigra with age, whereas adrenal TH mRNA increased with age. We propose that prolactin initially exerts a stimulatory effect on the TIDA neurons as the rat ages, but eventually causes a loss in neuronal number and neuronal function as the pituitary prolactinoma secretes increased amounts of prolactin.
Brain Res Mol Brain Res 1990 Jun
PMID:Tyrosine hydroxylase messenger RNA in the hypothalamus, substantia nigra and adrenal medulla of old female rats. 197 16

To clarify the effects of bromocriptine on prolactinoma cells in vivo, immunohistochemical, ultrastructural and morphometrical analyses were applied to estrogen-induced rat prolactinoma cells 1 h and 6 h after injection of bromocriptine (3 mg/kg of body weight). One h after treatment, serum prolactin levels decreased markedly. Electron microscopy disclosed many secretory granules, slightly distorted rough endoplasmic reticulum, and partially dilated Golgi cisternae in the prolactinoma cells. Morphometric analysis revealed that the volume density of secretory granules increased, while the volume density of cytoplasmic microtubules decreased. These findings suggest that lowered serum prolactin levels in the early phase of bromocriptine treatment may result from an impaired secretion of prolactin due to decreasing numbers of cytoplasmic microtubules. At 6 h after injection, serum prolactin levels were still considerably lower than in controls. The prolactinoma cells at this time were well granulated, with vesiculated rough endoplasmic reticulum and markedly dilated Golgi cisternae. Electron microscopical immunohistochemistry revealed positive reaction products noted on the secretory granules, Golgi cisternae, and endoplasmic reticulum of the untreated rat prolactinoma cells. However, only secretory granules showed the positive reaction products for prolactin 6 h after bromocriptine treatment of the adenoma cells. An increase in the volume density of secretory granules and a decrease in the volume densities of rough endoplasmic reticulum and microtubules was determined by morphometric analysis, suggesting that bromocriptine inhibits protein synthesis as well as bringing about a disturbance of the prolactin secretion.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Immunohistochemical, electron microscopic and morphometric studies of estrogen-induced rat prolactinomas after bromocriptine treatment. 288 62

It is now well known that dopamine (DA) plays a major role in the inhibitory control of prolactin (PRL); however, the mechanisms that are physiologically involved in the stimulation of PRL release are still under investigation. Indeed, although suppression of DA inhibitory tonus, administration of thyrotropin-releasing hormone (TRH) or vasoactive intestinal peptide (VIP) are all known PRL releasers, it is not clear whether they interact during physiological periods of PRL release such as suckling and estrus. No clear indications exist, furthermore, on whether they all act upon a same pituitary pool that may become depleted following repeated exposure to stimuli. Refractoriness to a single or a repeated stimulus has been reported to occur in prolactinoma-bearing or normal humans, respectively, the mechanism of which is still matter for discussion. Our present studies performed by perifusing normal or adenomatous rat lactotrophs attached to Cytodex I microcarrier beads was undertaken to try and answer some of these questions. The experimental period consisted in perifusing the cells for 1 h with Dulbecco's modified Eagle's medium (DMEM) containing DA 10(-5) M, then for 2 h with either DMEM, DMEM and TRH 10(-8) M, DMEM and VIP 10(-7) M, then again with DA in DMEM for 1 h, and finally with DMEM, DMEM and TRH, or DMEM and VIP. Three experiments of various combinations were performed. Lower PRL levels were observed under DA, while two periods (first and second) of PRL release followed the suppression of DA infusion with or without the addition of either one of the two peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1986 Sep
PMID:Effects of repeated stimuli on prolactin release in vitro from normal and adenomatous rat lactotrophs. 309 27

Hypersecretion of human GH (hGH) or PRL by human pituitary adenomas is not under normal homeostatic control despite normal receptor function mediating the regulatory effects of hypothalamic peptides for these trophic hormones. This implies that the defects underlying hormonal hypersecretion may not reside at the plasma membrane of the adenoma cell; instead, dysregulation may reside at the hormone gene level. To investigate this, genomic DNA derived from a prolactinoma and a hGH-secreting adenoma were digested with the restriction endonuclease EcoRI and the methylation sensitive restriction endonuclease HpaII and hybridized with the 32P-labeled genomic hGH (2.6 kilobase) probe. Our data revealed hypomethylation of genes of the hGH family (hGH and chorionic somatomammotropin) in the absence of gross abnormalities such as gene translocation. In a similar analysis using a 32P-labeled probe consisting of the EcoRI-BamHI (500 base pair) fragment in the 5'-flanking region upstream of the first exon of the hGH gene, hypomethylation of this specific site of the hGH genes was observed. These results are consistent with the concept that hypomethylation of genes is involved in gene expression. At the same time, protooncogene abnormalities in these adenomas were investigated to delineate any genetic basis for their neoplastic growth. Genomic DNA of adenomas were subjected to Southern blotting analysis using a panel of protooncogene probes. Amplification of the v-fos gene was observed in one prolactinoma. The significance of this observation is discussed.
Mol Endocrinol 1988 Jan
PMID:Abnormalities of the human growth hormone gene and protooncogenes in some human pituitary adenomas. 339 45

Using a combination of polymerase chain reaction and genomic library screening we have cloned a human gene for a subtype of the somatostatin (SST) receptor (SSTR) termed human SSTR5 (hSSTR5), which is located on chromosome 16. The predicted amino acid sequence of hSSTR5 displays 75% sequence identity with a recently identified rat SSTR [Mol. Pharmacol. 42:939-946 (1992)], suggesting that it is the human homologue of this receptor. hSSTR5 consists of a 363-residue polypeptide exhibiting a putative seven-transmembrane domain topology typical of G protein-coupled receptors. The receptor displays considerable sequence identity to hSSTR1 (42%), hSSTR2 (48%), hSSTR3 (47%), and hSSTR4 (46%). Membranes prepared from COS-7 cells transiently expressing the hSSTR5 gene bound 125I-Leu8,D-Trp22,Tyr25-SST-28 (125I-LTT-SST-28) with high affinity and in a saturable manner. SST-14, SST-28, and various synthetic SST peptide agonists produced dose-dependent inhibition of radioligand binding with the following rank order of potency: LTT-SST-28 > SST-28 > D-Trp8-SST-14 > SST-14 approximately RC-160 approximately BIM 23014 > MK-678 > SMS 201-995. hSSTR5 bound SST-28 with a 12.6-fold greater affinity (Ki = 0.19 nM), compared with SST-14 (Ki = 2.24 nM), indicating that the receptor is SST-28 selective. Addition of GTP, guanosine-5'-O-(3-thio)triphosphate, Na+ ions, or pertusis toxin greatly reduced 125I-LTT-SST-28 binding, thereby indicating that hSSTR5 is coupled to pertussis toxin-sensitive G proteins. Both SST-14 and SST-28 displayed dose-dependent inhibition of forskolin-stimulated cAMP accumulation, consistent with functional coupling of the receptor to adenylyl cyclase inhibition. Northern blot analysis of SSTR5 mRNA revealed a 2.4-kilobase transcript in normal rat pituitary and GH3 rat pituitary tumor cells and a 4.0-kilobase transcript in normal human pituitary. Reverse transcriptase polymerase chain reaction revealed expression of the hSSTR gene in fetal human pituitary and hypothalamus but not in human cerebral cortex. In situ hybridization of the rat pituitary showed that SSTR5 mRNA is selectively localized in the anterior lobe. SSTR5 mRNA was not expressed in four human pituitary tumors (somatotroph adenoma, prolactinoma, and chromophobe adenomas) or in a human insulinoma. Although hSSTR5 displays approximately 75% sequence identity with rat SSTR5, the two receptors display significantly different pharmacological profiles, especially with respect to their binding affinities for the SST analogue SMS 201-995.
Mol Pharmacol 1994 Mar
PMID:Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28. 790 5

Experiments were designed to examine whether vasoactive intestinal polypeptide (VIP), a known stimulator of basal prolactin (PRL) secretion, regulates PRL gene expression in the rat diethylstilbestrol (DES)-induced prolactinoma model. The VIP-induced increase in PRL release could result from increased PRL synthesis and/or decreased PRL degradation. Male Fischer 344 rats were implanted with 10 mg DES pellets 40 or 110 days prior to obtaining the anterior pituitary glands for cell dispersal. Cells were incubated in 1:10 normal rabbit serum or VIP antiserum (AVIP). After incubation, cells were pelleted, washed, and pooled for total nucleic acid extraction. The rat PRL (rPRL) mRNA abundance was quantitated using a solution hybridization/ribonuclease protection assay. Supernatant was collected and analyzed for PRL content using radioimmunoassay. Results from this experiment reveal partial immunoneutralization of intrapituitary VIP significantly decreased PRL secretory rate by rapid reduction in rRPL mRNA in the 40-day tumors. However, in the 110-day tumors the rPRL mRNA steady-state levels were unchanged but the basal release of PRL continued to be decreased by AVIP. These results indicate VIP exerts its effects on PRL secretion through at least two mechanisms.
Mol Cell Neurosci 1994 Apr
PMID:Vasoactive intestinal polypeptide antiserum affects rat prolactin mRNA in 40-day but not 110-day diethylstilbestrol-induced prolactinoma tissue. 803 86

Adenomas can develop from each cell type of the anterior pituitary. In the normal pituitary, three of these cells types, the GH-, prolactin- and TSH-secreting cells, express the transcription factor Pit-1/GHF-1 which is responsible for prolactin and GH (and probably TSH) cell commitment, differentiation, probably proliferation and gene expression. We have analysed the expression of Pit-1/GHF-1 in a panel of human pituitary adenomas. All GH-, prolactin- and TSH-expressing adenomas studied expressed the Pit-1/GHF-1 factor, as demonstrated by in-situ hybridization and immunocytochemistry. The expression was higher in adenomas than in normal human pituitary. In contrast, ACTH- and LH-FSH-secreting and non-secreting adenomas were negative. Seven transplants of the spontaneous rat prolactinoma SMtTW were also investigated and all were found to be positive. This further stresses the analogy between these tumours and human prolactinomas. Taken together, the data confirm that Pit-1/GHF-1 expression is restricted to GH-, prolactin- and TSH-expressing cells, and the increased expression in adenomas is compatible with a role of Pit-1/GHF-1 in cell proliferation.
J Mol Endocrinol 1993 Oct
PMID:Pit-1/GHF-1 expression in pituitary adenomas: further analogy between human adenomas and rat SMtTW tumours. 829 69

Two different human prolactinoma phenotypes (responders and nonresponders), which are distinguished by different tumorigenic potential and different responsiveness to dopaminergic therapy, have recently been identified. Responders show low proliferation rate, low tumorigenic potential, and expression of D-2 receptors for dopamine (DA), while nonresponders are characterized by high proliferation rate, high tumorigenic potential, and lack of expression of DA D-2 receptors. In this study it has been shown that both gp140trk and gp75 components of nerve growth factor (NGF) receptor are expressed in responder prolactinoma cell lines. High levels of both NGF gene transcript and protein were also found in responders, and biologically active NGF was detectable in the media conditioned by these cells. Ablation of NGF production in responder cells by hybridization arrest of translation through NGF antisense oligonucleotides resulted in: 1) loss of secreted NGF; 2) loss of expression of gp75; 3) loss of expression of DA D-2 receptors; and 4) a remarkable increase in the cell proliferation rate. These results thus suggest that a NGF-mediated autocrine loop essential to control cell proliferation and to preserve some phenotypical characteristics of mammotroph cells is present in responder prolactinoma cell lines. Analysis of nonresponders showed that these cells express gp140trk but no detectable levels of gp75. In addition, no NGF mRNA or protein was detectable in nonresponders. Exposure of these cells to NGF resulted in the permanent expression of NGF mRNA and in the production and secretion of NGF protein, thus establishing the same NGF-mediated autocrine loop present in responders. As a result, it has been shown that nonresponder cells treated with NGF acquire and maintain most of the phenotypic characteristics of normal mammotroph cells. In conclusion, the present work reports that a NGF-mediated autocrine loop with an inhibitory role in the control of cell proliferation and tumor progression is active in the more differentiated DA-sensitive prolactinoma cell lines and is lost in the most malignant prolactinoma cells refractory to the dopaminergic therapy. Alterations in the expression of this autocrine loop thus may lead to cell transformation and tumor progression.
Mol Endocrinol 1996 Mar
PMID:Nerve growth factor controls proliferation and progression of human prolactinoma cell lines through an autocrine mechanism. 883 56


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