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PubMed2000

Expression of prolactin and prolactin receptors by non-Hodgkin's lymphoma cells.

Prolactin (PRL) interacts with lymphocyte-signaling molecules and cytokines. Previous work has shown independent and synergistic effects of PRL on the generation of IL-2-driven anti-tumor lymphokine activated killer (LAK) activity by peripheral blood mononuclear cells (PBMC). The potential importance of PRL as a biological immunomodifier, however, is challenged by its ability to influence normal lymphocyte mitogenesis and hence lymphoid tumor growth. Since non-Hodgkin's lymphoma (NHL) cell lines were efficiently killed by LAK generated with native (n) or recombinant (r) human PRL combined with low, per se ineffective doses of IL-2, we have addressed here the question of whether PRL acts as a growth factor for LAK targets. NHL cells were analyzed for: 1. expression of the PRL receptor (PRL-R); 2. responsiveness to nPRL or rPRL; 3. constitutive expression and release of PRL; 4. existence of a PRL autocrine loop. PRL-R, defined by multiple antibodies, was detected in 3 of 12 NHL cell lines. However, nPRL or rPRL, in a wide range of concentrations (0.75-50 ng/ml), were not mitogenic for growth-arrested, PRL-R positive NHL cell lines. PRL mRNA was detected by RT-PCR in 10 of the 12 cell lines examined with a higher frequency among AIDS-related NHL cell lines. PRL protein in the immunoprecipitate of (35)S-methionine-labeled cell lysates and supernatants paralleled mRNA expression, and Western blotting analysis showed the presence of the pituitary/lymphocyte non-glycosylated (23.5 kDa) and glycosylated (25 kDa) isoforms. Experiments with blocking antibodies showed the independence from endogenous PRL for NHL cell growth.

Antibodies, Blocking↗

PubMed1988

High tumour prolactin receptor content and lack of increase in serum prolactin levels as predictors of good response to endocrine therapy in rat mammary cancer.

Correlations between anti-neoplastic activity of medroxyprogesterone acetate (MPA), on the one hand, and serum prolactin (PRL) levels as well as tumour PRL and insulin receptor content, on the other, were investigated in female rats bearing dimethylbenzanthracene (DMBA)-induced mammary tumours. Changes in liver PRL receptor concentrations were also studied. MPA was injected for 15 days. Regression was observed in 16 out of 50 (32%) tumours from rats treated with MPA. Twenty-seven out of 50 (54%) continued to grow regardless of treatment. Stasis was seen in the remaining 7 tumours (14%). Serum PRL levels increased significantly in rats with tumours which were non-responsive to MPA. Concentration of PRL receptors in the liver of all animals was reduced by MPA treatment. A remarkable increase occurred only in those mammary tumours which responded to therapy. The concentrations of PRL receptors in the tumours non-responsive to MPA were similar to those detected in control tumours. Unlike PRL receptors, tumour insulin receptor levels were not modified by MPA treatment. Five out of 14 tumours (35.7%), previously growing in spite of MPA administration, regressed when bromocriptine was added to MPA. A significant reduction in serum PRL levels occurred in all rats undergoing the latter treatment. No difference was observed between responsive and non-responsive animals; on the contrary, the PRL receptor content of responsive tumours increased significantly in comparison with that of non-responsive tumours.

Adenocarcinoma↗

PubMed1993

Effects of prolactin, growth hormone, and triiodothyronine on prolactin receptors in larval and adult tiger salamanders (Ambystoma tigrinum).

The effects of porcine growth hormone (pGH) or ovine prolactin (oPRL) alone and in combination with triiodothyronine (T3) on renal PRL receptors were determined in both pre- and post-metamorphic tiger salamanders (Ambystoma tigrinum). The protein hormones were given at a dose of 1.0 micrograms/gm body weight/day and the T3 was given at 10.0 ng/gm body weight/day. The duration of treatment was 7 days. Effects on growth, and plasma thyroid hormone levels were also determined. Ovine PRL increased growth in both larvae and adults and reversed metamorphic changes. Administration of T3 increased the plasma T3 concentration, as measured by radioimmunoassay, and when given alone caused weight loss at both stages. The GH decreased plasma T4 and increased plasma T3 concentrations, indicating that it caused an increase in T4 deiodination. In adults the renal PRL receptor affinity of 2.9 +/- 0.7 x 10(10) L/mol and capacity of 160 +/- 22 fmol/mg protein were higher than the corresponding values of 1.8 +/- 0.3 x 10(10) L/mol and 29.2 +/- 3.8 fmol/mg in larvae. In adults only, there is an additional low-affinity, high capacity PRL binding site. The oPRL treatment decreased the binding capacity of 33.2 +/- 1.2 and 5.9 +/- 4.9 fmol/mg in adults and larvae, respectively. By contrast, pGH increased the capacities to 249 +/- 18 and 62.1 +/- 6.8 fmol/mg in adults and larvae, respectively. Treatment with T3 alone doubled the oPRL binding capacity to 58.3 +/- 4.7 fmol/mg in larvae, but there was no effect in adults. In both developmental stages the effects of oPRL and pGH on the receptors were not changed by the simultaneous T3 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Ambystoma↗

PubMed1999

Human epidermal keratinocytes upregulate expression of the prolactin receptor after the onset of terminal differentiation, but do not respond to prolactin.

Growing and differentiating keratinocytes maintain the epidermal barrier. This is partly controlled by growth factors and hormones. Prolactin (PRL) is named after its hormonal role in mammals during lactation, but is found in all vertebrates where PRL exerts various effects. In serum-free keratinocyte cultures, PRL was thought to be the factor responsible for the proliferative effect of bovine pituitary extract. Here, we evaluated PRL as a clonogenic factor for keratinocytes and found no mitogenic activity. Studying the expression of the PRL receptor by keratinocytes, we found the receptor upregulated only after culture confluence, in differentiating keratinocytes, but we were unable to detect any cellular response to PRL. The hormone does not alter the gene expression of either early (suprabasal keratin) or late (involucrin) differentiation markers by keratinocytes. Accordingly, no activation of the transcription factor Stat5 by PRL can be detected in keratinocytes, Stat5 being nevertheless detected by Western blot.

Binding Sites↗

PubMed1994

Mechanism of prolactin action on the dissociation of prolactin from rabbit mammary gland receptor.

In order to elucidate the action of prolactin (PRL) on the dissociation of PRL from the receptor, Triton-solubilized and concanavalin A-purified rabbit mammary gland PRL receptor was immobilized onto a nitrocellulose membrane, and the dissociation of PRL was determined in the presence of PRL. PRL accelerated the dissociation of PRL in a concentration dependent manner for the first 3 h of incubation. The effects of PRL on dissociation were independent of the occupancy of PRL at the zero-time dissociation. In particular, PRL-dependency was influenced by the PRL-binding capacity of the membrane. The dissociation reaction was PRL-independent in the low-binding capacity membrane, indicating that PRL itself had no accelerating actions. With greater binding capacity, the dissociation reaction was seen to become PRL-dependent. It was concluded that PRL accelerated the dissociation of PRL through the formation of PRL-receptor complex when the receptor was located closely to the neighboring receptors.

Animals↗

PubMed2000

Involvement of prolactin-releasing peptide in the preovulatory luteinizing hormone and prolactin surges in the rat.

Prolactin (PRL)-releasing peptide (PrRP) is a novel hypothalamic peptide reported as a potent and specific stimulator of PRL secretion. In this study, we examined a possible role of PrRP in the ovarian steroid-induced PRL surge in the rat, simultaneously observing the change in luteinizing hormone (LH) surge. Experiments were performed on both normally-fed and three-day-fasted rats, which were ovariectomized and primed with estradiol and progesterone. From 11:00 to 18:00 h, blood was collected every 30 min to measure LH and PRL. All the following substances were given intracerebroventricularly at 11:00 h. Compared to control serum, anti-rat PrRP31 serum caused a significant reduction of the LH and PRL surges. The antiserum also delayed the onset of PRL surge. Fasted rats were devoid of significant surges of the hormones, while 3.0, but not 0.5 nmol of rat PrRP31 given to these animals produced a significant recovery of PRL surge. Although LH surge was not reinstated, basal LH secretion was transiently stimulated by 3.0 nmol of PrRP31. These results demonstrate for the first time a significant participation of PrRP in the preovulatory LH and PRL surges in the rat. Possible indirect pathways mediating this effect of PrRP were discussed, in view of the unique anatomical distribution of PrRP in the hypothalamus.

Animals↗

PubMed2002

Isolation and characterization of a homologue of mammalian prolactin-releasing peptide from the tilapia brain and its effect on prolactin release from the tilapia pituitary.

In the tilapia (Oreochromis mossambicus), as in many teleosts, prolactin (PRL) plays a major role in osmoregulation in freshwater. Recently, PRL-releasing peptides (PrRPs) have been characterized in mammals. Independently, a novel C-terminal RF (arginine-phenylalanine) amide peptide (Carrasius RF amide; C-RFa), which is structurally related to mammalian PrRPs, has been isolated from the brain of the Japanese crucian carp. The putative PrRP was purified from an acid extract of tilapia brain by affinity chromatography with antibody against synthetic C-RFa and HPLC on a reverse-phase ODS-120 column. The tilapia PrRP cDNA was subsequently cloned by polymerase chain reaction. The cDNA consists of 619 bp encoding a preprohormone of 117 amino acids. Sequence comparison of the isolated peptide and the preprohormone revealed that tilapia PrRP contains 20 amino acids and is identical to C-RFa. Incubation of the tilapia pituitary with synthetic C-RFa (100 nM) significantly stimulated the release of two forms of tilapia PRL (PRL188 and PRL177). However, the effect of C-RFa was less pronounced than the marked increase in PRL release in response to hyposmotic medium. The ability of C-RFa to stimulate PRL release appears to be specific, since C-RFa failed to stimulate growth hormone release from the pituitary in organ culture. In contrast, rat and human PrRPs had no effect on PRL release. C-RFa was equipotent with chicken GnRH in stimulating PRL release in the pituitary preincubated with estradiol 17beta. Circulating levels of PRL were significantly increased 1 h after intraperitoneal injection of 0.1 microg/g of C-RFa in female tilapia in freshwater but not in males. These results suggest that C-RFa is physiologically involved in the control of PRL secretion in tilapia.

Amino Acid Sequence↗

PubMed1998

The effect of exogenous testosterone on parental behavior, plasma prolactin, and prolactin binding sites in dark-eyed juncos.

Numerous studies have shown that parental behaviors are mediated by prolactin (PRL), while testosterone (T) interferes with their full expression. The limited data available suggest that reduced parental behavior induced by T is not mediated by reduced concentrations of plasma PRL. We hypothesized that T reduces parental behaviors by reducing PRL receptor binding activity at central neural sites that promote the expression of parental behaviors. To test this hypothesis we implanted male dark-eyed juncos (Junco hyemalis) with testosterone-filled or empty implants and measured T and PRL levels, paternal behavior, and specific binding of radio-labeled PRL at selected brain regions that have been implicated in the mediation of parental behaviors. Our findings concurred with previous studies in that T-treated males reduced their parental contributions, had higher levels of T, and had equivalent levels of PRL compared with controls. We found no differences in the capacity to bind 125I-oPRL in three brain regions previously implicated in the mediation of parental care in birds, i.e., the preoptic area, ventromedial nucleus of the hypothalamus, and paraventricular nucleus of the hypothalamus. Thus our findings do not support the hypothesis that T interferes with the expression of parental behavior by reducing PRL receptor binding activity at central sites.

Animals↗

PubMed2005

Development of a prolactin receptor-targeting fusion toxin using a prolactin antagonist and a recombinant form of Pseudomonas exotoxin A.

Human prolactin (hPRL) promotes the proliferation and differentiation of mammary epithelial cells during mammary gland development and has been linked to breast tumor development. The receptor for hPRL (hPRL-R) is elevated in a majority of human breast tumors, suggesting the overexpression of hPRL-R makes cancer cells highly sensitive to the mitogenic and anti-apoptotic activity of hPRL. These findings provide the rationale for the development of hPRL-R targeting breast cancer therapeutics. Previously, an hPRL-R antagonist, G129R, was developed that competitively binds to the hPRL-R resulting in growth inhibition and the induction of apoptosis in certain types of breast cancer cells. To further increase the potency of G129R, we fused G129R to a truncated form of Pseudomonas exotoxin A (PE(40)) that lacks the cell recognition domain of the toxin but retains the domains necessary for PE(40)_ to translocate into the cytosol and inhibit protein synthesis. We postulated that the fusion of G129R with PE(40)-KDEL would (1) deliver the recombinant toxin to breast cancer cells where hPRL-R is overexpressed; (2) block hPRL signaling via its G129R moiety; and (3) inhibit protein synthesis via its PE(40)-KDEL moiety. We demonstrate that the fusion toxin can competitively bind to hPRL-Rs on T-47D human breast cancer cells and inhibit STAT5 phosphorylation induced by hPRL. In addition, we show that G129R-PE(40)-KDEL is selectively cytotoxic to breast cancer cell lines expressing the hPRL-R and that cell death is associated with the inhibition of protein synthesis and does not involve caspase mediated apoptosis.

Bacterial Proteins↗

PubMed1992

Radioreceptor assay of serum prolactin using nitrocellulose membrane-immobilized mammary prolactin receptor.

Triton-solubilized rabbit mammary prolactin (PRL) receptor was purified by concanavalin A-agarose chromatography and immobilized on a nitrocellulose membrane. Using the membrane-bound receptor and bovine serum, the serum level of PRL was determined by radioreceptor assay (RRA). The displacement curve, obtained by serial dilutions of the serum, was parallel to that obtained in the range of 0.4 and 20 ng/ml of standard bovine PRL. Serum could be included in concentrations up to 16% of the assay buffer and, thus, the detection limit of serum PRL was about 2.5 ng/ml. PRL in the serum was determined by radioimmunoassay (RIA). The ratio of the RIA and RRA estimates of PRL was 0.99 (r = +0.99, n = 55). The gel-filtration profile of serum PRL was identical to that obtained by RIA. It was concluded that membrane-bound receptor can be used for the determination of serum PRL.

Animals↗

PubMed1984

Prolactin receptors in tilapia (Sarotherodon mossambicus) tissues: binding studies using 125I-labeled ovine prolactin.

The binding of 125I-labeled ovine prolactin (oPRL) to membrane preparations of tissue from freshwater-adapted tilapia (Sarotherodon mossambicus) was examined. Liver, ovary, and testis showed a relatively high specific binding (5-10%). A lower specific binding occurred consistently in intestine and gill tissue, and inconsistently in urinary bladder and kidney preparations. Desaturation experiments with MgCl2 indicated that a majority of the PRL receptors were already occupied by endogenous PRL. Scatchard analysis of liver binding gave a dissociation constant of 0.6 X 10(-9) M and a capacity of 207 fmol/mg protein.

Animals↗

PubMed1987

Circadian alterations in prolactin, corticosterone, and thyroid hormone levels and down-regulation of prolactin receptor activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Studies were initiated to determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects circadian rhythms of serum prolactin (PRL), corticosterone, thyroxine (T4), and triiodothyronine (T3) in male Sprague-Dawley rats. In addition, the effects of TCDD on PRL receptor activity, as assessed by the ability of PRL to induce ornithine decarboxylase (ODC), were determined. The earliest effect detected following TCDD administration was a significant decrease in the serum PRL concentration compared with that of pair-fed controls within 4 hr (p less than 0.05). This was followed by a significant decrease in serum T4 by 6 hr (p less than 0.05). By 8 hr the serum peak of corticosterone was shifted to 2 hr later in the TCDD-treated rats. This temporal sequence of hormonal changes suggests that the earlier alteration in PRL may be involved in the later alterations in the concentrations of serum T4 and corticosterone. The serum PRL concentration 7 days after TCDD administration was significantly higher (p less than 0.05) in TCDD-treated animals compared with that in pair-fed controls (mean of 20.5 +/- 3.7 vs 13.6 +/- 1.8 ng/ml serum, p less than 0.05, respectively). The elevation of ODC activity in response to PRL, 2 days after TCDD, was decreased in the order of thymus greater than adrenal greater than spleen greater than heart greater than kidney greater than liver. By 7 days, liver ODC activity in response to PRL was only 12% that detected in pair-fed controls. Liver ODC activity in response to dexamethasone and aminophylline was decreased to 25 and 22% of pair-fed controls, respectively, by 7 days after TCDD administration. However, in kidney, TCDD-treated rats had an increased ODC response to aminophylline to 191% of pair-fed controls by Day 7. These results suggest that the ability of TCDD to alter receptor coupling or the receptor number for diverse hormones may play a role in TCDD toxicity.

Aminophylline↗

PubMed1995

Morphine-induced prolactin release precedes a down-regulation of prolactin receptors in the male rat choroid plexus and hypothalamus.

In previous studies we provided evidence for changes in prolactin (PRL) receptor levels in the male rat brain after continuously infusing morphine using subcutaneously implanted miniosmotic pumps. In this work we have studied the binding of PRL in the male rat brain following morphine administration by both subcutaneous (s.c.) and intracerebroventricular (i.c.v.) injections. The binding in the choroid plexus and the hypothalamus was measured using iodinated ovine PRL (oPRL) as a radiolabel. The results indicated that the density of the PRL-binding sites in the hypothalamus and the choroid plexus were significantly decreased 4 h and 24 h after s.c. injections, and also 30 min and 4 h after i.c.v. injections. However, no decrease in PRL-binding was observed 15 min after i.c.v. injection of morphine. The plasma levels of PRL were measured by radioimmunoassay (RIA) and were found to be significantly increased after 30 min and 4 h in all treated animals. Following i.c.v. injection a significant increase in plasma PRL was observed after just 15 min. It was suggested that the down-regulation in PRL binding to some extent at least resulted from receptor overstimulation caused by the morphine-induced elevation in the concentrations of the endogenous hormone.

Animals↗

PubMed1985

Induction of prolactin receptors by prolactin in the rat lung and liver: demonstration of separate receptor and antibody entities.

This study examined the role of prolactin (PRL) in inducing its own receptors in rat lung and liver beyond the parallel immunological response evoked. Ovine PRL (oPRL), mixed with polyvinylpyrrolidone (PVP) and injected s.c. daily to male rats for 7, 10 and 14 days, was shown to induce specific binding of [125I]iodo-oPRL in the lung and liver crude membrane fractions. Doses as low as 12.5 ng/kg were effective in inducing PRL-binding sites, which, however, differed qualitatively from those found in livers of 17 beta-estrogen-treated male rats. The oPRL-induced sites were highly specific for oPRL and were relatively stable to heat, suggesting the possible participation of antihormone antibodies in the binding observed. Indeed, anti-oPRL antibodies found in sera of oPRL-treated rats increasingly bound oPRL as a function of the duration of treatment. Water-washing of the membrane fraction succeeded in gradually eliminating the loosely bound antibody and in partially restoring the displacing ability of excess (1 micrograms) rat PRL on oPRL-binding sites in the lung (32.3%) and liver membranes (29.3%). Also restored were the heat lability typical of the receptor site, as well as the inhibitory effect of anti-PRL-receptor antiserum (1:100) on PRL binding (50-65% inhibition of total binding). In keeping with these results, in vitro incubation of liver membranes with rat anti-oPRL antiserum greatly reduced the ability of rat PRL to compete for oPRL binding, supporting the findings after in vivo treatment with oPRL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Prolactin stimulates milk protein promoter in CHO cells cotransfected with prolactin receptor cDNA.

A functional biological system was developed by cotransfecting mammalian cell lines with the cDNA of the prolactin receptor (PRL-R) and a fusion gene containing the promoter of the milk protein, ovine beta-lactoglobulin linked to the coding sequence of the chloramphenicol acetyltransferase (CAT) gene. Surprisingly, this system is effective even if a non-mammary cell line is used, since Chinese hamster ovary (CHO) cells transfected both transiently and stably with PRL-R cDNA respond to PRL, as observed by stimulation of the reporter gene. This newly developed system should help precisely define the functional domains of both the PRL-R molecule and of the regulatory elements of a PRL target gene.

Animals↗

PubMed2004

Molecular cloning of bullfrog prolactin receptor cDNA: changes in prolactin receptor mRNA level during metamorphosis.

In amphibian larvae, prolactin (PRL) is known to possess growth-promoting and anti-metamorphic activities. For further understanding of the role of PRL in larvae, bullfrog PRL receptor (bfPRLR) cDNA was obtained from the tail fin of premetamorphic tadpoles by use of the reverse transcription-polymerase chain reaction (RT-PCR) coupled with 5' - and 3' -rapid amplification of cDNA ends (RACE). The predicted bfPRLR was composed of 617 amino acids, contained a single transmembrane domain, and showed 33-57% sequence homologies with known sequences of vertebrate PRLRs. When bfPRLR was transiently expressed, specific binding of 125I-labeled bullfrog PRL (bfPRL) was observed. By Northern blot analysis, a 3-kb transcript was detected in the tail fin. By RT-PCR bfPRLR mRNA expression was detected mainly in the brain, kidney, skin, and tail throughout prometamorphic and middle climactic periods. The results of an RNase protection assay revealed that the bfPRLR mRNA level in the tail fin increased around the onset of climax (stage XX) and was maintained at a relatively high value at least until mid-climax (stage XXII). It also revealed that bfPRLR mRNA level in the kidney of larvae gradually rose as metamorphosis progressed. The results support the view that PRL in larval period acts not only on the larval organs but also on the organs that are necessary for the adult life to maintain or develop their structures and functions.

Amino Acid Sequence↗

PubMed2006

Prolactin and prolactin receptor expressions in a marine teleost, pufferfish Takifugu rubripes.

To investigate the physiological significance of prolactin (PRL) in a marine teleost, pufferfish (or fugu), Takifugu rubripes, we cloned and characterized cDNAs encoding its PRL and PRL receptor (PRLR) from the pituitary and gills, respectively. The fugu PRL cDNA consisted of 995 bp and encoded a protein of 213 amino acids. The PRLR, consisting of 510 amino acids, contained a putative signal peptide, an extracellular domain with two pairs of cysteines, a WSXWS motif, a single transmembrane domain, and a cytoplasmic (intracellular) domain with box 1 and box 2 regions, all of which are characteristic of the cytokine receptor superfamily. Reverse transcription-PCR showed the expression of PRLR mRNA in osmoregulatory organs, such as gills, kidney, and intestine, whereas pufferfish PRL mRNA was detected only in the pituitary. Furthermore, in situ hybridization revealed the expression of pufferfish PRLR in branchial chloride cells, kidney tubule cells, and intestinal epithelia. The PRL-gene expression levels in the pituitary were about five times higher in 25%-diluted seawater than in full-strength seawater. These results suggest that fugu PRL regulates water and electrolyte balances through PRLR expressed in the osmoregulatory organs, as is the case with freshwater-adapted euryhaline species.

Amino Acid Sequence↗

PubMed2000

Evaluation of the role for prolactin-releasing peptide in prolactin secretion induced by ether stress and suckling in the rat: comparison with vasoactive intestinal peptide.

Prolactin (PRL)-releasing peptide (PrRP) is a recently discovered hypothalamic peptide possessing a specific stimulatory action on PRL secretion. In this study, we examined whether PrRP plays a role in mediating ether stress- and suckling-induced PRL secretion in rats through administering anti-PrRP antisera intracerebroventricularly. For comparison, we also tested the effect of anti-vasoactive intestinal peptide (VIP) antisera on the hormonal responses, since VIP is another candidate for a physiological PRL-releasing factor. The immunoneutralization of VIP, but not of PrRP, led to a significant suppression of PRL responses to both ether and suckling. These results suggest that PrRP may not play a significant role, or at least play a much weaker role than VIP, in mediating PRL release induced by ether stress and suckling in the rat.

Animals↗