title: Mutant polycystin-2 induces proliferation in primary rat tubular epithelial cells in a STAT-1/p21-independent fashion accompanied instead by alterations in expression of p57KIP2 and Cdk2.
abstract: BACKGROUND
  Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that destroy the kidney architecture resulting in end-stage renal failure. Mutations in genes PKD1 and PKD2 account for nearly all cases of ADPKD. Increased cell proliferation is one of the key features of the disease. Several studies indicated that polycystin-1 regulates cellular proliferation through various signaling pathways, but little is known about the role played by polycystin-2, the product of PKD2. Recently, it was reported that as with polycystin-1, polycystin-2 can act as a negative regulator of cell growth by modulating the levels of the cyclin-dependent kinase inhibitor, p21 and the activity of the cyclin-dependent kinase 2, Cdk2.
  
  
  METHODS
  Here we utilized different kidney cell-lines expressing wild-type and mutant PKD2 as well as primary tubular epithelial cells isolated from a PKD transgenic rat to further explore the contribution of the p21/Cdk2 pathway in ADPKD proliferation.
  
  
  RESULTS
  Surprisingly, over-expression of wild-type PKD2 in renal cell lines failed to inactivate Cdk2 and consequently had no effect on cell proliferation. On the other hand, expression of mutated PKD2 augmented proliferation only in the primary tubular epithelial cells of a rat model but this was independent of the STAT-1/p21 pathway. On the contrary, multiple approaches revealed unequivocally that expression of the cyclin-dependent kinase inhibitor, p57KIP2, is downregulated, while p21 remains unchanged. This p57 reduction is accompanied by an increase in Cdk2 levels.
  
  
  CONCLUSIONS
  Our results indicate the probable involvement of p57KIP2 on epithelial cell proliferation in ADPKD implicating a new mechanism for mutant polycystin-2 induced proliferation. Most importantly, contrary to previous studies, abnormal proliferation in cells expressing mutant polycystin-2 appears to be independent of STAT-1/p21.
authors: Department of Biological Sciences, University of Cyprus, Cyprus. deltas@ucy.ac.cy
authors: Kyriacos N
authors: KN
authors: Felekkis
authors: Panayiota
authors: P
authors: Koupepidou
authors: Evdokia
authors: E
authors: Kastanos
authors: Ralph
authors: R
authors: Witzgall
authors: Chang-Xi
authors: CX
authors: Bai
authors: Li
authors: L
authors: Li
authors: Leonidas
authors: L
authors: Tsiokas
authors: Norbert
authors: N
authors: Gretz
authors: Constantinos
authors: C
authors: Deltas
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D002455:Cell Division; D002460:Cell Line / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007684:Kidney Tubules / Q000473:pathology; D008564:Membrane Potentials; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D050396:TRPP Cation Channels; D014162:Transfection; D054462:p21-Activated Kinases / Q000502:physiology
chemical_list: D051357:Cyclin-Dependent Kinase 2; D050761:Cyclin-Dependent Kinase Inhibitor p57; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D050396:TRPP Cation Channels; D054462:p21-Activated Kinases; C494081:Stat1 protein, rat; C515906:Pak1 protein, rat; C495892:Cdk2 protein, rat