From the molecular biology of prolactin and its receptor to the lessons learned from knockout mice models

Goffin, Vincent; Binart, Nadine; Clément-Lacroix, Philippe; Bouchard, Brigitte; Bôle‐Feysot, Christine; Edery, Marc; Lucas, Brian K.; Touraine, Philippe; Pezet, Alain; Maaskant, Ronda A.; Pichard, C.; Helloco, Christine; Baran, Nathalie; Favre, H.; Bernichtein, Sophie; Allamando, Angelique; Ormandy, Christopher J.; Kelly, Paul A.

doi:10.1016/s1050-3862(99)00025-x

Cited by 77 publications

(42 citation statements)

References 89 publications

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“…Lactogen-induced anti-apoptotic BCLXL, is required for its pro-survival effect against GLT-mediated cell death in rodent beta cells The anti-apoptotic member of the BCL family of molecules, BCLXL, is a known transcriptional target of lactogens and STAT5 activation in many cell types [15,26]. Further, we have shown that BCLXL protein is upregulated in INS-1 cells in response to PRL [26].…”

Section: Resultsmentioning

confidence: 63%

“…Therefore, finding ways to reduce GLT-mediated beta cell loss would have a significant bearing on patients with diabetes. Prolactin (PRL) and placental lactogen (PL), members of the lactogenic family of peptide hormones, act through a common PRL receptor (PRL-R), which belongs to the class 1 cytokine receptor superfamily [15,16]. PRL-R is expressed in the beta cell of rodent and human islets [17,18].…”

mentioning

confidence: 99%

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Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

et al. 2012

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Aims/hypothesis A leading cause of type 2 diabetes is a reduction in functional beta cell mass partly due to increased beta cell death, triggered by stressors such as glucolipotoxicity (GLT). This study evaluates the hypothesis that lactogens can protect beta cells against GLT and examines the mechanism behind the pro-survival effect. Methods The effect of exogenous treatment or endogenous expression of lactogens on GLT-induced beta cell death was examined in INS-1 cells, and in rodent and human islets. The mechanism behind the pro-survival effect of lactogens was determined using an inhibitor, siRNAs, a dominant negative (DN) mutant, and Cre-lox-mediated gene deletion analysis. Results Lactogens significantly protect INS-1 and primary rodent beta cells against GLT-induced cell death. The prosurvival effect of lactogens in rodent beta cells is mediated through activation of the Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling pathway. Lactogen-induced increase in the anti-apoptotic B cell lymphoma-extra large (BCLXL) protein is required to mediate its pro-survival effects in both INS-1 cells and primary rodent beta cells. Most importantly, lactogens significantly protect human beta cells against GLT-induced cell death, and their prosurvival effect is also mediated through the JAK2/STAT5 pathway. Conclusions/interpretation These studies, together with previous work, clearly demonstrate the pro-survival nature of lactogens and identify the JAK2/STAT5 pathway as an important mediator of this effect in both rodent and human beta cells. Future studies will determine the effectiveness of this peptide in vivo in the pathophysiology of type 2 diabetes.

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Section: Resultsmentioning

confidence: 63%

mentioning

confidence: 99%

Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

et al. 2012

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“…The intermediate form of the rPRLR has only been found in the Nb2 lymphoma cell line, whereas the long and short isoforms are expressed in normal tissues (Goffin & Kelly 1997). Previous studies revealed the ubiquitous expression of both the long and short isoforms of the PRLR in the rat (Goffin et al 1999). However, expression ratio of the long and short isoforms is dependent on tissue type and physiological state of the animal, with PRLR long form being predominant in most tissues (Nagano & Kelly 1994).…”

Section: Introductionmentioning

confidence: 99%

Prolactin receptor expression in the epithelia and stroma of the rat mammary gland

Camarillo¹,

Thórdarson²,

Moffat³

et al. 2001

Journal of Endocrinology

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The importance of prolactin (PRL) in regulating growth and differentiation of the mammary gland is well known. However, it is not well established whether PRL acts solely on the mammary epithelia or if it can also directly affect the mammary stroma. To determine where PRL could exert its effects within the mammary gland, we investigated the levels of expression and the localization of the PRL receptor (PRLR) in the epithelia and stroma of the rat mammary gland at different physiological stages. For these studies, we isolated parenchymal-free 'cleared' fat pads and intact mammary glands from virgin, 18-daypregnant and 6-day-lactating rats. In addition, intact mammary tissues were enzymatically digested to obtain epithelial cells, free of stroma. The mammary tissues, intact gland, stroma and isolated epithelia, were then used for immunocytochemistry, protein extraction and isolation of total RNA. PRLR protein was detected in tissues using specific polyclonal antisera (PRLR-l) by immunocytochemistry and Western blot analysis. Messenger RNA for PRLR was measured by ribonuclease protection assay. Immunocytochemistry and Western blots with the PRLR-1 antisera detected PRLR in wild-type rat and mouse tissues, whereas the receptor protein was absent in tissues from PRLR gene-deficient mice. PRLR was found to be present both in the epithelia and stroma of mammary glands from virgin, pregnant and lactating rats, as determined by immunocytochemistry and Western blotting. Western blots revealed the predominance of three bands migrating at 88, 90 and 92 kDa in each of the rat mammary samples. These represent the long form of the PRLR. During pregnancy and lactation, PRLR protein increased in the epithelial compartment of the mammary gland but did not change within the stromal compartment at any physiological stage examined. We also found PRLR mRNA in both the epithelia and stroma of the mammary gland. Again, the stroma contained lower levels of PRLR mRNA compared with the epithelia at all physiological stages examined. Also, the PRLR mRNA levels within the stroma did not change significantly during pregnancy or lactation, whereas PRLR mRNA within the epithelia increased twofold during pregnancy and fourfold during lactation when compared with virgin rats. We conclude from this study that PRLR is expressed both in the stromal and epithelial compartment of the mammary gland. This finding suggests PRL may have a direct affect on the mammary stroma and by that route affect mammary gland development.

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“…There is clinical and experimental evidence suggesting that the prolactin response to orgasm may not only affect reproductive organs (Outhit et al 1993, Bole-Feysot et al 1998, Goffin et al 1999, but also play a role in the control of acute sexual arousal following orgasm. Supporting this position, chronic elevations of prolactin (hyperprolactinemia), induced by prolactin-secreting tumors or as a side effect of typical neuroleptics, produce pronounced reductions of sexual drive and gonadal functions in animals (Doherty et al 1986) and humans (Yazigi et al 1997, Hummer et al 1999, Knegtering et al 2003.…”

Section: Introductionmentioning

confidence: 99%

Effects of acute prolactin manipulation on sexual drive and function in males

Krüger

Haake²,

Haverkamp³

et al. 2003

Journal of Endocrinology

126

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The neuroendocrine response to sexual activity in humans is characterized by a pronounced orgasm-dependent increase of plasma levels of prolactin. In contrast to the well-known inhibitory effects of chronic hyperprolactinemia on sexual drive and function, the impact of acute prolactin alterations on human sexual physiology is unknown. Therefore, this study was designed to investigate the effects of acute manipulation of plasma prolactin on sexual behavior.Ten healthy males participated in a single-blind, placebo-controlled, balanced cross-over design. Prolactin levels were pharmacologically increased to high levels (protirelin, 50 µg i.v.) or reduced to low physiological concentrations (cabergoline, 0·5 mg p.o.). Sexual arousal and orgasm were then induced by an erotic film and masturbation. In addition to continuous neuroendocrine and cardiovascular recordings, the quality and intensity of the acute sexual drive, arousal, orgasm and refractory period were assessed by extensive psychometric measures.Administration of cabergoline decreased prolactin levels and significantly enhanced all parameters of sexual drive (P,0·05), function (P,0·01) and positive perception of the refractory period (P,0·01). Administration of protirelin increased prolactin concentrations and produced small, but not significant reductions of sexual parameters. The sexual effects observed from cabergoline were completely abrogated by coadministration of protirelin.Although different pharmacological sites of action of prolactin-altering drugs have to be considered, these data demonstrate that acute changes in prolactin plasma levels may be one factor modulating sexual drive and function. Therefore, besides a neuroendocrine reproductive reflex, a post-orgasmic prolactin increase may represent one factor modulating central nervous system centers controlling sexual drive and behavior. These findings may offer a new pharmacological approach for the treatment of sexual disorders.

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From the molecular biology of prolactin and its receptor to the lessons learned from knockout mice models

Cited by 77 publications

References 89 publications

Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

Prolactin receptor expression in the epithelia and stroma of the rat mammary gland

Effects of acute prolactin manipulation on sexual drive and function in males

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