title: Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells.
abstract: Contrary to cell cycle-associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-dependent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks.
authors: Department of Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors: Julia
authors: J
authors: Lindqvist
authors: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors: Susumu Y
authors: SY
authors: Imanishi
authors: Department of Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors: Elin
authors: E
authors: Torvaldson
authors: Institute of Biomedicine/Medical Biochemistry, University of Eastern Finland, and Department of Pathology, Kuopio University Hospital, FI-70211 Kuopio, Finland.
authors: Marjo
authors: M
authors: Malinen
authors: Department of Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland.
authors: Mika
authors: M
authors: Remes
authors: Department of Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland.
authors: Fanny
authors: F
authors: Örn
authors: Institute of Biomedicine/Medical Biochemistry, University of Eastern Finland, and Department of Pathology, Kuopio University Hospital, FI-70211 Kuopio, Finland.
authors: Jorma J
authors: JJ
authors: Palvimo
authors: Department of Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland john.eriksson@abo.fi.
authors: John E
authors: JE
authors: Eriksson
mesh_terms: D049109:Cell Proliferation; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt; C495905:CDK5 protein, human