title: Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.
abstract: OBJECTIVE
  To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression.
  
  
  METHODS
  We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer.
  
  
  RESULTS
  Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K-Ras (G12D) that involves mitogen-activated protein/extracellular signal-regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels.
  
  
  CONCLUSIONS
  These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Eggers
authors.forename: Paul M
authors.initials: PM
authors.lastname: Grandgenett
authors.forename: Eric C
authors.initials: EC
authors.lastname: Collisson
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Lewallen
authors.forename: Jarrod
authors.initials: J
authors.lastname: Tremayne
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Swanson
authors.forename: Judy M
authors.initials: JM
authors.lastname: Andersen
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Caffrey
authors.forename: Robin R
authors.initials: RR
authors.lastname: High
authors.forename: Michel
authors.initials: M
authors.lastname: Ouellette
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D005784:Gene Amplification; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C500695:CDCA5 protein, human; C108298:Cdk5 activator p39; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D011687:Purines; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5