title: Prolactin stimulates cell proliferation through a long form of prolactin receptor and K+ channel activation.
abstract: PRL (prolactin) has been implicated in the proliferation and differentiation of numerous tissues, including the prostate gland. However, the PRL-R (PRL receptor) signal transduction pathway, leading to the stimulation of cell proliferation, remains unclear and has yet to be mapped. The present study was undertaken to develop a clear understanding of the mechanisms involved in this pathway and, in particular, to determine the role of K(+) channels. We used androgen-sensitive prostate cancer (LNCaP) cells whose proliferation is known to be stimulated by PRL. Reverse transcriptase PCR analysis showed that LNCaP cells express a long form of PRL-R, but do not produce its intermediate isoform. Patch-clamp techniques showed that the application of 5 nM PRL increased both the macroscopic K(+) current amplitude and the single K(+)-channel open probability. This single-channel activity increase was reduced by the tyrosine kinase inhibitors genistein, herbimycin A and lavandustine A, thereby indicating that tyrosine kinase phosphorylation is required in PRL-induced K(+) channel stimulation. PRL enhances p59( fyn ) phosphorylation by a factor of 2 after a 10 min application in culture. In addition, where an antip59( fyn ) antibody is present in the patch pipette, PRL no longer increases K(+) current amplitude. Furthermore, the PRL-stimulated proliferation is inhibited by the K(+) channel inhibitors alpha-dendrotoxin and tetraethylammonium. Thus, as K(+) channels are known to be involved in LNCaP cell proliferation, we suggest that K(+) channel modulation by PRL, via p59( fyn ) pathway, is the primary ionic event in PRL signal transduction, triggering cell proliferation.
authors.affiliation: Laboratoire de Physiologie Cellulaire, INSERM EMI 0228, Université des Sciences et Technologies de Lille, Bât. SN3, 59655 Villeneuve d'Ascq Cedex, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Van Coppenolle
authors.forename: Roman
authors.initials: R
authors.lastname: Skryma
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
authors.forename: Christian
authors.initials: C
authors.lastname: Slomianny
authors.forename: Morad
authors.initials: M
authors.lastname: Roudbaraki
authors.forename: Philippe
authors.initials: P
authors.lastname: Delcourt
authors.forename: Etienne
authors.initials: E
authors.lastname: Dewailly
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humez
authors.forename: Alexandre
authors.initials: A
authors.lastname: Crépin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourdou
authors.forename: Jean
authors.initials: J
authors.lastname: Djiane
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Bonnal
authors.forename: Brigitte
authors.initials: B
authors.lastname: Mauroy
authors.forename: Natalia
authors.initials: N
authors.lastname: Prevarskaya
mesh_terms: D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003600:Cytosol / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D011981:Receptors, Prolactin / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D009363:Neoplasm Proteins; D015221:Potassium Channels; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D011388:Prolactin; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D002118:Calcium