Prolactin—a novel neuroendocrine regulator of human keratin expression in situ

The controls of human keratin expression in situ remain to be fully elucidated. Here, we have investigated the effects of the neurohormone prolactin (PRL) on keratin expression in a physiologically and clinically relevant test system: organ‐cultured normal human hair follicles (HFs). Not only do HFs express a wide range of keratins, but they are also a source and target of PRL. Microarray analysis revealed that PRL differentially regulated a defined subset of keratins and keratin‐associated proteins. Quantitative immunohistomorphometry and quantitative PCR confirmed that PRL up‐regulated expression of keratins K5 and K14 and the epithelial stem cell‐associated keratins K15 and K19 in organ‐cultured HFs and/or isolated HF keratinocytes. PRL also up‐regulated K15 promoter activity and K15 protein expression in situ, whereas it inhibited K6 and K31 expression. These regulatory effects were reversed by a pure competitive PRL receptor antagonist. Antagonist alone also modulated keratin expression, suggesting that “tonic stimulation” by endogenous PRL is required for normal expression levels of selected keratins. Therefore, our study identifies PRL as a major, clinically relevant, novel neuroendocrine regulator of both human keratin expression and human epithelial stem cell biology in situ. —Ramot, Y., Bíro´, T., Tiede, S. To´th, B. I., Langan, E. A., Sugawara, K., Foitzik, K., Ingber, A., Goffin, V., Langbein, L., Paus, R. Prolactin—a novel neuroendocrine regulator of human keratin expression in situ. FASEB J. 24, 1768–1779 (2010). www.fasebj.org

[1]  Y. Ramot,et al.  Mind the (gender) gap: does prolactin exert gender and/or site-specific effects on the human hair follicle? , 2010, The Journal of investigative dermatology.

[2]  Y. Ramot,et al.  Thyrotropin releasing hormone (TRH): a new player in human hair‐growth control , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  C. Kruse,et al.  Nestin in human skin: exclusive expression in intramesenchymal skin compartments and regulation by leptin. , 2009, The Journal of investigative dermatology.

[4]  E. Gáspár,et al.  The ‘melanocyte‐keratin’ mystery revisited: neither normal human epidermal nor hair follicle melanocytes express keratin 16 or keratin 6 in situ , 2009, The British journal of dermatology.

[5]  R. Paus,et al.  Nonviral In Situ Green Fluorescent Protein Labeling and Culture of Primary, Adult Human Hair Follicle Epithelial Progenitor Cells , 2009, Stem cells.

[6]  A. Knight,et al.  A novel mutation (p.Thr198Ser) in the 1A helix of keratin 5 causes the localized variant of Epidermolysis Bullosa Simplex , 2009, Experimental dermatology.

[7]  R. Paus,et al.  Human female hair follicles are a direct, nonclassical target for thyroid-stimulating hormone. , 2009, The Journal of investigative dermatology.

[8]  R. Paus,et al.  Prolactin and the skin: a dermatological perspective on an ancient pleiotropic peptide hormone. , 2009, The Journal of investigative dermatology.

[9]  Y. Ramot,et al.  Endocrine controls of keratin expression , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[10]  H. Mollenkopf,et al.  A human folliculoid microsphere assay for exploring epithelial- mesenchymal interactions in the human hair follicle. , 2009, The Journal of investigative dermatology.

[11]  M. Arin.  The molecular basis of human keratin disorders , 2009, Human Genetics.

[12]  Raphael Kopan,et al.  Genetic interplays between Msx2 and Foxn1 are required for Notch1 expression and hair shaft differentiation. , 2009, Developmental biology.

[13]  Ralf Paus,et al.  The Hair Follicle as a Dynamic Miniorgan , 2009, Current Biology.

[14]  R. Paus,et al.  Thyroid hormones directly alter human hair follicle functions: anagen prolongation and stimulation of both hair matrix keratinocyte proliferation and hair pigmentation. , 2008, The Journal of clinical endocrinology and metabolism.

[15]  C. Jackson,et al.  Autocrine actions of matrix metalloproteinase (MMP)-2 counter the effects of MMP-9 to promote survival and prevent terminal differentiation of cultured human keratinocytes. , 2008, The Journal of investigative dermatology.

[16]  R. Paus,et al.  Immunophenotyping of the human bulge region: the quest to define useful in situ markers for human epithelial hair follicle stem cells and their niche , 2008, Experimental dermatology.

[17]  P. Arck,et al.  (Neuro-)endocrinology of epithelial hair follicle stem cells , 2008, Molecular and Cellular Endocrinology.

[18]  R. Moll,et al.  The human keratins: biology and pathology , 2008, Histochemistry and Cell Biology.

[19]  X. Tong,et al.  Vibrissa hair bulge houses two populations of skin epithelial stem cells distinct by their keratin profile , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  M. Laugsch,et al.  Human hair follicles are an extrarenal source and a nonhematopoietic target of erythropoietin , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  B. Strober,et al.  Management of psoriasis in pregnancy , 2013, Dermatologic therapy.

[22]  H. Winter,et al.  Hair follicle-specific keratins and their diseases. , 2007, Experimental cell research.

[23]  N. Reynolds,et al.  Management of psoriasis in pregnancy , 2007, BMJ : British Medical Journal.

[24]  J. Østergaard.  Mind the Gender Gap! , 2007 .

[25]  P. Coulombe,et al.  Keratin function in skin epithelia: a broadening palette with surprising shades. , 2007, Current opinion in cell biology.

[26]  R. Paus,et al.  Differential expression of HPA axis homolog in the skin , 2007, Molecular and Cellular Endocrinology.

[27]  P. Schirmacher,et al.  K25 (K25irs1), K26 (K25irs2), K27 (K25irs3), and K28 (K25irs4) represent the type I inner root sheath keratins of the human hair follicle. , 2006, The Journal of investigative dermatology.

[28]  S. Gadd,et al.  Ligand-independent dimerization of the human prolactin receptor isoforms: functional implications. , 2006, Molecular endocrinology.

[29]  P. Kelly,et al.  Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia? , 2006, Nature Clinical Practice Endocrinology &Metabolism.

[30]  D. Tobin,et al.  Corticotropin releasing hormone and the skin. , 2006, Frontiers in bioscience : a journal and virtual library.

[31]  E. Birgitte Lane,et al.  New consensus nomenclature for mammalian keratins , 2006, The Journal of cell biology.

[32]  G. Cotsarelis.  Epithelial stem cells: a folliculocentric view. , 2006, The Journal of investigative dermatology.

[33]  J. Gustafsson,et al.  The hair follicle as an estrogen target and source. , 2006, Endocrine reviews.

[34]  P. Coulombe,et al.  A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth , 2006, Nature.

[35]  R. Paus,et al.  Human scalp hair follicles are both a target and a source of prolactin, which serves as an autocrine and/or paracrine promoter of apoptosis-driven hair follicle regression. , 2006, The American journal of pathology.

[36]  J. Schweizer,et al.  Characterization of a novel human type II epithelial keratin K1b, specifically expressed in eccrine sweat glands. , 2005, The Journal of investigative dermatology.

[37]  R. Paus,et al.  Human hair follicles display a functional equivalent of the hypothalamic‐pituitary‐adrenal (HPA) axis and synthesize cortisol , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  R. Hovey,et al.  Prolactin-induced expression of vascular endothelial growth factor via Egr-1 , 2005, Molecular and Cellular Endocrinology.

[39]  D. Tobin,et al.  The cutaneous serotoninergic/melatoninergic system: securing a place under the sun , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  M. Soares.  The prolactin and growth hormone families: Pregnancy-specific hormones/cytokines at the maternal-fetal interface , 2004, Reproductive biology and endocrinology : RB&E.

[41]  D. Tobin,et al.  beta-Endorphin as a regulator of human hair follicle melanocyte biology. , 2004, The Journal of investigative dermatology.

[42]  E. Gootwine.  Placental hormones and fetal-placental development. , 2004, Animal reproduction science.

[43]  O. Stojadinović,et al.  Thyroid Hormones and Gamma Interferon Specifically Increase K15 Keratin Gene Transcription , 2004, Molecular and Cellular Biology.

[44]  H. Winter,et al.  Androgen regulation of the human hair follicle: the type I hair keratin hHa7 is a direct target gene in trichocytes. , 2004, The Journal of investigative dermatology.

[45]  J. Martial,et al.  Development of Pure Prolactin Receptor Antagonists* , 2003, Journal of Biological Chemistry.

[46]  A. Slominski,et al.  Self-regulated endocrine systems in the skin. , 2003, Minerva Endocrinologica.

[47]  R. Paus,et al.  Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen. , 2003, The American journal of pathology.

[48]  S. Hankinson,et al.  The role of prolactin in mammary carcinoma. , 2003, Endocrine reviews.

[49]  L. French,et al.  Organotypic cultures of autologous hair follicle keratinocytes for the treatment of recurrent leg ulcers. , 2003, Journal of the American Academy of Dermatology.

[50]  C. Chuong,et al.  `Cyclic alopecia' in Msx2 mutants: defects in hair cycling and hair shaft differentiation , 2003, Development.

[51]  A. Nixon,et al.  Regulation of prolactin receptor expression in ovine skin in relation to circulating prolactin and wool follicle growth status. , 2002, The Journal of endocrinology.

[52]  C. Zouboulis.  Human Skin: An Independent Peripheral Endocrine Organ , 2001, Hormone Research in Paediatrics.

[53]  J. Mazurkiewicz,et al.  Cutaneous expression of corticotropin‐releasing hormone (CRH), urocortin, and CRH receptors , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[54]  R. Wilkins,et al.  Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice. , 2001, Endocrinology.

[55]  T. Ito,et al.  Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia. , 2001, Development.

[56]  R. Brown,et al.  Lactation affects expression of intermediate filaments in human breast epithelium. , 2001, Differentiation; research in biological diversity.

[57]  R. Paus,et al.  Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. , 2000, Physiological reviews.

[58]  R Paus,et al.  The biology of hair follicles. , 1999, The New England journal of medicine.

[59]  R. Paus,et al.  What controls hair follicle cycling? , 1999, Experimental dermatology.

[60]  L Langbein,et al.  The Catalog of Human Hair Keratins , 1999, The Journal of Biological Chemistry.

[61]  D. Elder,et al.  The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. , 1998, Journal of cell science.

[62]  P. Kelly,et al.  Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. , 1998, Endocrine reviews.

[63]  S. Watanabe,et al.  Keratin and involucrin expression in discoid lupus erythematosus and lichen planus , 1997, Archives of Dermatological Research.

[64]  M. Lussier,et al.  Keratin 19 as a biochemical marker of skin stem cells in vivo and in vitro: keratin 19 expressing cells are differentially localized in function of anatomic sites, and their number varies with donor age and culture stage. , 1996, Journal of cell science.

[65]  I. Leigh,et al.  Keratin expression in cutaneous lichen planus , 1995, Histopathology.

[66]  P. Dicks,et al.  The role of prolactin in the reactivation of hair follicles in relation to moulting in cashmere goats. , 1994, The Journal of endocrinology.

[67]  S. Ewen,et al.  Growth of secondary hair follicles of the Cashmere goat in vitro and their response to prolactin and melatonin. , 1994, Journal of anatomy.

[68]  L. Hu,et al.  Activation of keratin 19 gene expression by a 3' enhancer containing an AP1 site. , 1994, The Journal of biological chemistry.

[69]  O. Rascol,et al.  Alopecia: an adverse effect of bromocriptine. , 1993, Clinical neuropharmacology.

[70]  M. Green,et al.  Human hair growth in vitro. , 1990, Journal of cell science.

[71]  A. Limat,et al.  Post-mitotic human dermal fibroblasts efficiently support the growth of human follicular keratinocytes. , 1989, The Journal of investigative dermatology.

[72]  A. Limat,et al.  Serial cultivation of single keratinocytes from the outer root sheath of human scalp hair follicles. , 1986, The Journal of investigative dermatology.

[73]  A. Lupulescu.  Enhancement of epidermal carcinoma formation by prolactin in mice. , 1985, Journal of the National Cancer Institute.

[74]  L. Martinet,et al.  Role of prolactin in the photoperiodic control of moulting in the mink (Mustela vison). , 1984, The Journal of endocrinology.

[75]  B. Goldman,et al.  Hormonal regulation of the annual pelage color cycle in the Djungarian hamster, Phodopus sungorus. II. Role of prolactin. , 1984, The Journal of experimental zoology.

[76]  B. Goldman,et al.  Hormonal regulation of the annual pelage color cycle in the Djungarian hamster, Phodopus sungorus. I. Role of the gonads and pituitary. , 1984, The Journal of experimental zoology.

[77]  I. Blum,et al.  Increased hair loss as a side effect of bromocriptine treatment. , 1980, The New England journal of medicine.

[78]  Elaine Fuchs,et al.  Changes in keratin gene expression during terminal differentiation of the keratinocyte , 1980, Cell.

[79]  G. Kallergi,et al.  Phosphorylation of FAK, PI-3K, and Impaired Actin Organization in CK-positive Micrometastatic Breast Cancer Cells , 2007, Molecular medicine.

[80]  J. Schweizer,et al.  Keratins of the human hair follicle. , 2005, International review of cytology.

[81]  D. Mischke,et al.  Normal psoriatic epidermis expression of hyperproliferation-associated keratins , 2004, Archives of Dermatological Research.

[82]  C. Zouboulis.  The human skin as a hormone target and an endocrine gland. , 2004, Hormones.

[83]  J. Visvader,et al.  Investigation of the transcriptional changes underlying functional defects in the mammary glands of prolactin receptor knockout mice. , 2003, Recent progress in hormone research.

[84]  P. Kelly,et al.  Prolactin: the new biology of an old hormone. , 2002, Annual review of physiology.

[85]  S. Ma,et al.  Transcriptional control of K5, K6, K14, and K17 keratin genes by AP-1 and NF-kappaB family members. , 1997, Gene expression.

[86]  V. Choy,et al.  Inhibitory effect of increased photoperiod on wool follicle growth. , 1996, The Journal of endocrinology.

[87]  J. Schmidt.  Hormonal basis of male and female androgenic alopecia: clinical relevance. , 1994, Skin pharmacology : the official journal of the Skin Pharmacology Society.

[88]  P. Kelly,et al.  0163-769X/05/$20.00/0 Endocrine Reviews 26(3):400–422 Printed in U.S.A. Copyright © 2005 by The Endocrine Society doi: 10.1210/er.2004-0016 Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists , 2022 .