Disease relevance of Prl

• A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone [1].
• A mouse model of isolated PRL deficiency (PRL-/-) was created by gene disruption in an effort to further understand the molecular basis of mammary gland development and breast cancer [2].
• An absence of nuclear translocation of PRLR was also observed in a 293 cell line stably expressing the receptor, and in physiological targets for PRL, i.e. in Nb2 lymphoma cells expressing the Nb2 form of the receptor or in BGME mammary gland epithelial cells upon overexpression of a Flag-tagged PRLR [3].
• We are reporting that PRL deficiency does not affect the rate of weight gain, body composition, serum lipids, or adiponectin levels in either sex on any diet [4].
• In this report, we identify and characterize a new member of the rat PRL family, examine the impact of maternal hypoxia on placental PRL family gene expression, and investigate maternal adaptive responses to hypoxia [5].

Psychiatry related information on Prl

• Prolactin (PRL) is the primary lactogenic pituitary hormone that plays an essential role in many aspects of reproduction, from fertilization to mammary gland development and maternal behavior [6].
• Mice deficient in the interferon type I receptor have reduced REM sleep and altered hypothalamic hypocretin, prolactin and 2',5'-oligoadenylate synthetase expression [7].
• We showed recently that ghrelin promotes slow-wave sleep and the nocturnal release of GH, cortisol and prolactin in humans [8].
• Daily administration of bromocriptine, a suppressor of pituitary PRL secretion, increased the latency period and decreased the incidence of tumor development in HAN bearing mice [9].
• 0. When secreted mouse PRL was incubated in alkaline (pH 10.0) conditions at 25 C, ammonia was released as the conversion reaction occurred [10].

High impact information on Prl

• The phenotypes of the mice demonstrate an essential, and often redundant, role for the two Stat5 proteins in a spectrum of physiological responses associated with growth hormone and prolactin [11].
• The relationship between expression of the pituitary-specific transcription factor, GHF-1, and activation of the growth hormone and prolactin genes during mouse anterior pituitary development was investigated [12].
• Oxytocin, prolactin and hydrocortisone, which slowed or blocked involution, produced parallel effects on gland regression and PA synthesis [13].
• Plasma concentrations of luteinizing hormone, prolactin and sex steroids are low in these animals [14].
• Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion [15].

Chemical compound and disease context of Prl

• Our objectives were to compare: 1) weight gain, 2) body composition, 3) serum lipid profile, 4) circulating leptin and adiponectin levels, and 5) glucose tolerance in PRL knockout, heterozygous, and wild-type mice maintained on standard chow, high-fat, or low-fat diets [4].
• One of the earliest cellular responses to prolactin (PRL) binding in Nb2 cells, a rat pre-T lymphoma cell line, is an increase in tyrosine phosphorylation of cellular proteins [16].
• The present study suggests that PRL is an important factor in the development of prostate hyperplasia acting directly on the prostate gland or via increased plasma levels of testosterone [17].
• The prolactin (PRL)-like activity released into synthetic culture medium from concanavalin-A (Con-A)-stimulated mouse splenocytes was bioassayed using 3H thymidine incorporation into Nb2 lymphoma cells [18].
• We have previously reported a dramatic prostate enlargement with concurrent chronic hyperprolactinemia and elevated serum androgen levels in a PRL transgenic mouse (Mt-PRL) with ubiquitous expression of the transgene [19].

Biological context of Prl

• One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes [1].
• In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection [1].
• Prolactin-mediated gene activation in mammary epithelial cells [20].
• The prolactin (PRL) family gene cluster is one of 25 mouse-specific gene clusters, the majority of which are associated with reproduction [21].
• Prolactin (PRL) plays a central and crucial role in the regulation of milk protein gene expression in mammary epithelial cells [22].

Anatomical context of Prl

• Dominant-negative Rac1 prevents Prl-induced synthesis of the milk protein beta-casein in primary mammary epithelial cells cultured as three-dimensional acini on basement membrane [23].
• Specific inhibition of GHF1 synthesis by complementary oligonucleotides led to a marked decrease in GH and PRL expression and to a marked decrease in proliferation of somatotrophic cell lines [24].
• These dwarf mice (dw and dwJ) are deficient in growth hormone (GH) and prolactin (PRL) synthesis and exhibit pituitary hypoplasia, suggesting a stem cell defect [24].
• It is a nonclassical member of the PRL family (e.g., PLP-A does not use the PRL receptor) produced by trophoblast cells of the chorioallantoic placenta and acts on uterine natural killer cells [21].
• Moreover, we show that tyrosine phosphorylation of IRS-3 was induced by both GH and PRL in COS cells transiently transfected with IRS-3 and their cognate receptors [25].

Associations of Prl with chemical compounds

• In dwarfs supplemented postnatally with dietary thyroxine for 9 wks, the treatment failed to produce immunoreactive GH, TSH or Prl cells [26].
• We conclude that PRL inhibits lactotrophs by two distinct mechanisms: (a) indirectly by activation of hypothalamic dopamine neurons and (b) directly within the pituitary in a dopamine-independent fashion [27].
• These results demonstrate that JAK protein tyrosine kinases couple PRL binding to tyrosine phosphorylation and proliferation [28].
• Pregnancy, established by mating progesterone-treated PRL-/- females with PRL-/- males, led to complete morphological development of the mammary gland, appropriate to the gestational stage [2].
• Proliferin (PLF), a protein which has homology to PRL and GH, has been implicated in the regulation of cell growth and differentiation [29].

Physical interactions of Prl

• PRL binding to its cognate receptor leads to receptor dimerization and activation of the tyrosine kinase Janus kinase 2 (JAK2), associated with the membrane-proximal, intracellular domain of the receptor [22].
• Investigating possible mitogenic signaling pathways we show for the first time that prolactin is coupled to a sustained phospholipase D (PLD) activation, with an efficacy similar to the phorbol ester and astrocytic mitogen 12-tetradecanoylphorbol-13-acetate (TPA) [30].
• The above criteria suggest that the postpartum increase in PRL binding is characterized especially by an increase in the level of acid-insensitive PRL receptor located mainly on intracellular membrane [31].
• The MGF complexes formed upon initiation of lactation in the mammary gland and upon stimulation of mammary epithelial cells with PRL migrated at the same position in electrophoretic mobility shift assay, whereas the MGF complex found in mammary gland extracts of pregnant mice exhibited a faster mobility [32].
• Here, the complex actions of RIP140 and other AF-2-interacting proteins at the PRL enhancer/promoter were shown to operate via ER itself [33].

Enzymatic interactions of Prl

• A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b [22].
• We have previously shown that in HC11 mammary epithelial cells Stat5a is phosphorylated on Tyr(694) in a prolactin-sensitive manner, whereas serine phosphorylation is constitutive (Wartmann, M., Cella, N., Hofer, P., Groner, B., Xiuwen, L., Hennighausen, L., and Hynes, N. E. (1996) J. Biol. Chem. 271, 31863-31868) [34].

Regulatory relationships of Prl

• However, only in BAF-3 cells expressing the PRL-R does PRL induce rapid and transient tyrosine phosphorylation of JAK1 [28].
• Stat5b also induced basal transcription in the absence of PRL [35].
• The molecular mechanisms by which PRL may induce RANKL expression have not been carefully examined [36].
• Janus kinase 2 (JAK2) regulates prolactin-mediated chloride transport in mouse mammary epithelial cells through tyrosine phosphorylation of Na+-K+-2Cl- cotransporter [37].
• PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro [38].
• Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death [39].

Other interactions of Prl

• We used Drd2(-/-) and Prlr(-/-) mutant mice to bypass this feedback and investigate possible dopamine-independent effects of PRL on lactotroph function [27].
• Signals from basement membrane are transduced by beta1 integrins and are required for prolactin to activate DNA binding of the milk protein gene transcription factor, Stat5 [40].
• We identified a gamma-interferon activation sequence (GAS) in the region between residues -965 to -725 of the RANKL promoter, which conferred a PRL response [36].
• These results are the first demonstrations of a role for tyrosine phosphorylation of NKCC1 and of the PRL-JAK2 cascade in the regulation of Cl- transport [37].
• In this study, we provide evidence that part of the effect of PRL on mammary gland growth is mediated by IGF-II [38].

Analytical, diagnostic and therapeutic context of Prl

• The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied [1].
• Progesterone Receptor Repression of Prolactin/Signal Transducer and Activator of Transcription 5-Mediated Transcription of the {beta}-Casein Gene in Mammary Epithelial Cells [41].
• Immunofluorescence combined with detailed confocal laser microscopy showed that addition of PRL (0 to 12 hours) to COS-7, CHO and NIH-3T3 transfected fibroblasts induces rapid internalization of the receptor (long form), without any translocation to the nucleus [3].
• METHODS: In this study, the expression of PRL in the mouse kidney was investigated by solution-phase and in situ reverse transcription-polymerase chain reaction (RT-PCR) methods and immunohistochemistry [42].
• Trace amounts of mRNA for GlyCAM 1 were detected by RT-PCR in mammary tissue of PRL-/- mice [43].

References