title: Polycystin-1 transforms the cAMP growth-responsive phenotype of M-1 cells.
abstract: BACKGROUND
  Polycystic kidney disease (PKD) is characterized by the abnormal proliferation of tubular epithelial cells. It was recently shown that the growth of PKD cyst-lining cells is stimulated by cyclic adenosine monophosphate (cAMP), whereas the growth of normal human kidney cortex cells is inhibited.
  
  
  METHODS
  We have examined the effects of overexpressing the C-terminal cytosolic tail of mouse polycystin-1, as a membrane-targeted fusion protein, on cAMP-responsive cell proliferation in stably transfected M-1 cortical collecting duct cells. Two cell lines that express high levels of the polycystin-1 fusion protein and two control cell lines that do not express the fusion protein were tested.
  
  
  RESULTS
  Growth of parental M-1 cells and the control cell lines was inhibited by 8-Br-cAMP and by a variety of cAMP agonists. In contrast, growth of the polycystin-1-expressing clones was stimulated by cAMP. Consistent with this, the protein kinase A (PKA) inhibitor H-89 caused either a positive or a negative growth effect depending on the primary response to cAMP. PD98059 blocked the cAMP stimulation of cell proliferation, indicating that the pathway is MEK1 dependent.
  
  
  CONCLUSIONS
  Expression of the polycystin-1 C-terminal tail disrupts normal cellular signaling and transforms the stably transfected M-1 cells to an abnormal PKD cell proliferation phenotype.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sutters
authors.forename: T
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: R L
authors.initials: RL
authors.lastname: Maser
authors.forename: B S
authors.initials: BS
authors.lastname: Magenheimer
authors.forename: P L
authors.initials: PL
authors.lastname: St John
authors.forename: D R
authors.initials: DR
authors.lastname: Abrahamson
authors.forename: J J
authors.initials: JJ
authors.lastname: Grantham
authors.forename: J P
authors.initials: JP
authors.lastname: Calvet
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000166:cytology; D051379:Mice; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides; D050396:TRPP Cation Channels; D014162:Transfection
chemical_list: D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007546:Isoquinolines; D011506:Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D050396:TRPP Cation Channels; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one