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Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

INSERM Unité 344-Endocrinologie Moléculaire, Faculté de Médecine Necker, 75730 Paris Cedex 15, France

I. Introduction

II. PRL

A. The PRL/GH/PL family

B. PRL gene and primary structure

C. PRL tertiary structure

D. Extrapituitary PRL

III. PRL Receptor (PRLR)

A. The class 1 cytokine receptor superfamily

B. PRLR gene and primary structure

C. PRLR tertiary structure

D. PRLR binding and activation by PRL

IV. Distribution of the PRLRs

V. Biological Functions of PRL

A. Water and electrolyte balance

B. Growth and development

C. Endocrinology and metabolism

D. Brain and behavior

E. Reproduction

F. Immunoregulation and protection

G. Actions associated with pathological disease states

VI. Signal Transduction by the PRLR: Structure-Function Relationships

A. The JAK-Stat pathway

B. The Ras/Raf/MAP kinase pathway

C. Other signaling pathways

VII. Null Mutation of the PRLR Gene

A. Gene cloning, vector construction, and generation of PRLR^-/- mice

B. PRLR gene expression and PRLR protein in PRLR^-/- mice

C. Impaired mammary gland development and lactation in heterozygous females

D. Heterozygote maternal behavior

E. Homozygous females are sterile

F. Homozygous male fertility

G. Other gene-targeted mutations leading to impaired mammary gland and reproductive function

H. Other phenotypes of PRLR^-/- mice

VIII. Summary and Conclusions

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				R L Bogorad, T Y Ostroukhova, A N Orlova, P M Rubtsov, and O V Smirnova Long isoform of prolactin receptor predominates in rat intrahepatic bile ducts and further increases under obstructive cholestasis J. Endocrinol., February 1, 2006; 188(2): 345 - 354. [Abstract] [Full Text] [PDF]

				Z. Nouhi, N. Chughtai, S. Hartley, E. Cocolakis, J.-J. Lebrun, and S. Ali Defining the Role of Prolactin as an Invasion Suppressor Hormone in Breast Cancer Cells Cancer Res., February 1, 2006; 66(3): 1824 - 1832. [Abstract] [Full Text] [PDF]

				P. Kok, F. Roelfsema, J. G. Langendonk, C. C. de Wit, M. Frolich, J. Burggraaf, A. E. Meinders, and H. Pijl Increased circadian prolactin release is blunted after body weight loss in obese premenopausal women Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E218 - E224. [Abstract] [Full Text] [PDF]

				N. Nanashima, J. Asano, M. Hayakari, T. Nakamura, H. Nakano, T. Yamada, T. Shimizu, M. Akita, Y. Fan, and S. Tsuchida Nuclear Localization of STAT5A Modified with O-Linked N-Acetylglucosamine and Early Involution in the Mammary Gland of Hirosaki Hairless Rat J. Biol. Chem., December 30, 2005; 280(52): 43010 - 43016. [Abstract] [Full Text] [PDF]

				Y. Li, M. Wallis, and Y.-p. Zhang Episodic evolution of prolactin receptor gene in mammals: coevolution with its ligand J. Mol. Endocrinol., December 1, 2005; 35(3): 411 - 419. [Abstract] [Full Text] [PDF]

				F. Y. Ma, G. M. Anderson, T. D. Gunn, V. Goffin, D. R. Grattan, and S. J. Bunn Prolactin Specifically Activates Signal Transducer and Activator of Transcription 5b in Neuroendocrine Dopaminergic Neurons Endocrinology, December 1, 2005; 146(12): 5112 - 5119. [Abstract] [Full Text] [PDF]

				F. Obal Jr, F. Garcia-Garcia, B. Kacsoh, P. Taishi, S. Bohnet, N. D. Horseman, and J. M. Krueger Rapid Eye Movement Sleep Is Reduced in Prolactin-Deficient Mice J. Neurosci., November 2, 2005; 25(44): 10282 - 10289. [Abstract] [Full Text] [PDF]

				J.-C. Lu, T. M. Piazza, and L. A. Schuler Proteasomes Mediate Prolactin-induced Receptor Down-regulation and Fragment Generation in Breast Cancer Cells J. Biol. Chem., October 7, 2005; 280(40): 33909 - 33916. [Abstract] [Full Text] [PDF]

				J. Jensen, E. D Galsgaard, A. E Karlsen, Y. C Lee, and J. H Nielsen STAT5 activation by human GH protects insulin-producing cells against interleukin-1{beta}, interferon-{gamma} and tumour necrosis factor-{alpha}-induced apoptosis independent of nitric oxide production J. Endocrinol., October 1, 2005; 187(1): 25 - 36. [Abstract] [Full Text] [PDF]

				J. G. Miquet, A. I. Sotelo, A. Bartke, and D. Turyn Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice Am J Physiol Endocrinol Metab, October 1, 2005; 289(4): E600 - E607. [Abstract] [Full Text] [PDF]

				C. Kedzia, L. Lacroix, N. Ameur, T. Ragot, P. A. Kelly, B. Caillou, and N. Binart Medullary Thyroid Carcinoma Arises in the Absence of Prolactin Signaling Cancer Res., September 15, 2005; 65(18): 8497 - 8503. [Abstract] [Full Text] [PDF]

				J Bancroft The endocrinology of sexual arousal J. Endocrinol., September 1, 2005; 186(3): 411 - 427. [Abstract] [Full Text] [PDF]

				W. Wu, E. Ginsburg, B. K. Vonderhaar, and A. M. Walker S179D Prolactin Increases Vitamin D Receptor and p21 through Up-regulation of Short 1b Prolactin Receptor in Human Prostate Cancer Cells Cancer Res., August 15, 2005; 65(16): 7509 - 7515. [Abstract] [Full Text] [PDF]

				J. C. Hogan and J. M. Stephens The Regulation of Fatty Acid Synthase by STAT5A Diabetes, July 1, 2005; 54(7): 1968 - 1975. [Abstract] [Full Text] [PDF]

				T Sakamoto, M Amano, S Hyodo, S Moriyama, A Takahashi, H Kawauchi, and M Ando Expression of prolactin-releasing peptide and prolactin in the euryhaline mudskippers (Periophthalmus modestus): prolactin-releasing peptide as a primary regulator of prolactin J. Mol. Endocrinol., June 1, 2005; 34(3): 825 - 834. [Abstract] [Full Text] [PDF]

				V. Goffin, S. Bernichtein, P. Touraine, and P. A. Kelly Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists Endocr. Rev., May 1, 2005; 26(3): 400 - 422. [Abstract] [Full Text] [PDF]

				D. Tan, D. A. Johnson, W. Wu, L. Zeng, Y. H. Chen, W. Y. Chen, B. K. Vonderhaar, and A. M. Walker Unmodified Prolactin (PRL) and S179D PRL-Initiated Bioluminescence Resonance Energy Transfer between Homo- and Hetero-Pairs of Long and Short Human PRL Receptors in Living Human Cells Mol. Endocrinol., May 1, 2005; 19(5): 1291 - 1303. [Abstract] [Full Text] [PDF]

				T. Matsutani, T. S. A. Samy, L. W. Rue III, K. I. Bland, and I. H. Chaudry Transgenic prolactin-/- mice: effect of trauma-hemorrhage on splenocyte functions Am J Physiol Cell Physiol, May 1, 2005; 288(5): C1109 - C1116. [Abstract] [Full Text] [PDF]

				E. M. Johansson, M. Kannius-Janson, A. Gritli-Linde, G. Bjursell, and J. Nilsson Nuclear Factor 1-C2 Is Regulated by Prolactin and Shows a Distinct Expression Pattern in the Mouse Mammary Epithelial Cells during Development Mol. Endocrinol., April 1, 2005; 19(4): 992 - 1003. [Abstract] [Full Text] [PDF]

				C. Farmer and M.-F. Palin Exogenous prolactin stimulates mammary development and alters expression of prolactin-related genes in prepubertal gilts J Anim Sci, April 1, 2005; 83(4): 825 - 832. [Abstract] [Full Text] [PDF]

				T. E. Strecker, T. J. Spady, B. S. Schaffer, K. A. Gould, A. E. Kaufman, F. Shen, M. T. McLaughlin, K. L. Pennington, J. L. Meza, and J. D. Shull Genetic Bases of Estrogen-Induced Pituitary Tumorigenesis: Identification of Genetic Loci Determining Estrogen-Induced Pituitary Growth in Reciprocal Crosses Between the ACI and Copenhagen Rat Strains Genetics, April 1, 2005; 169(4): 2189 - 2197. [Abstract] [Full Text] [PDF]

				R. P. Piekorz, S. Gingras, A. Hoffmeyer, J. N. Ihle, and Y. Weinstein Regulation of Progesterone Levels during Pregnancy and Parturition by Signal Transducer and Activator of Transcription 5 and 20{alpha}-Hydroxysteroid Dehydrogenase Mol. Endocrinol., February 1, 2005; 19(2): 431 - 440. [Abstract] [Full Text] [PDF]

				F. Y. Ma, D. R. Grattan, V. Goffin, and S. J. Bunn Prolactin-Regulated Tyrosine Hydroxylase Activity and Messenger Ribonucleic Acid Expression in Mediobasal Hypothalamic Cultures: The Differential Role of Specific Protein Kinases Endocrinology, January 1, 2005; 146(1): 93 - 102. [Abstract] [Full Text] [PDF]

				S Viengchareun, H Bouzinba-Segard, J-P Laigneau, M-C Zennaro, P A Kelly, A Bado, M Lombes, and N Binart Prolactin potentiates insulin-stimulated leptin expression and release from differentiated brown adipocytes J. Mol. Endocrinol., December 1, 2004; 33(3): 679 - 691. [Abstract] [Full Text] [PDF]

				M. E C Amaral, D. A Cunha, G. F Anhe, M. Ueno, E. M Carneiro, L. A Velloso, S. Bordin, and A. C Boschero Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy J. Endocrinol., December 1, 2004; 183(3): 469 - 476. [Abstract] [Full Text] [PDF]

				J. H. Gutzman, D. E. Rugowski, M. D. Schroeder, J. J. Watters, and L. A. Schuler Multiple Kinase Cascades Mediate Prolactin Signals to Activating Protein-1 in Breast Cancer Cells Mol. Endocrinol., December 1, 2004; 18(12): 3064 - 3075. [Abstract] [Full Text] [PDF]

				Y. Fujinaka, D. Sipula, A. Garcia-Ocana, and R. C. Vasavada Characterization of Mice Doubly Transgenic for Parathyroid Hormone-Related Protein and Murine Placental Lactogen: A Novel Role for Placental Lactogen in Pancreatic {beta}-Cell Survival Diabetes, December 1, 2004; 53(12): 3120 - 3130. [Abstract] [Full Text] [PDF]