As an atypical member of cyclin dependent kinase family, Cyclin dependent kinase 5 (Cdk5) is considered as a neuron-specific kinase in the past decade due to the abundant existence of its activator p35 in post-mitotic neurons. Recent studies show that Cdk5 participates in a series of biological and pathological processes in non-neuronal cells, and is generally dysregulated in various cancer cells. The inhibition or knockdown of Cdk5 has been proven to play an anti-cancer role through various mechanisms, and can synergize the killing effect of chemotherapeutics. DNA damage response (DDR) is a series of regulatory events including DNA damage, cell-cycle arrest, regulation of DNA replication, and repair or bypass of DNA damage to ensure the maintenance of genomic stability and cell viability. Here we describe the regulatory mechanisms of Cdk5, its controversial roles in apoptosis and focus on its links to DDR and cancer.
Echalier A, Endicott JA, Noble ME. Recent developments in cyclin-dependent kinase biochemical and structural studies. Biochim Biophys Acta. 1804;2010:511–9.
Takasugi T, Minegishi S, Asada A, Saito T, Kawahara H, Hisanaga S. Two Degradation Pathways of the p35 Cdk5 (Cyclin-dependent Kinase) Activation Subunit. Dependent and Independent of Ubiquitination. 2016;291:4649–57.
Zuccotti P, Colombrita C, Moncini S, Barbieri A, Lunghi M, Gelfi C, De Palma S, Nicolin A, Ratti A, Venturin M, Riva P. hnRNPA2/B1 and nELAV proteins bind to a specific U-rich element in CDK5R1 3'-UTR and oppositely regulate its expression. Biochim Biophys Acta. 1839;2014:506–16.
Zheng YL, Amin ND, Hu YF, Rudrabhatla P, Shukla V, Kanungo J, Kesavapany S, Grant P, Albers W, Pant HC. A 24-residue peptide (p5), derived from p35, the Cdk5 neuronal activator, specifically inhibits Cdk5-p25 hyperactivity and tau hyperphosphorylation. J Biol Chem. 2010;285:34202–12. CrossRefPubMedPubMedCentral
Ouedraogo ZG, Biau J, Kemeny JL, Morel L, Verrelle P, Chautard E: Role of STAT3 in Genesis and Progression of Human Malignant Gliomas. Mol Neurobiol 2016. [Epub ahead of print]
Ogara MF, Belluscio LM, de la Fuente V, Berardino BG, Sonzogni SV, Byk L, Marazita M, Canepa ET. CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions. Biochim Biophys Acta. 1843;2014:1309–24.
Wei K, Ye Z, Li Z, Dang Y, Chen X, Huang N, Bao C, Gan T, Yang L, Chen G. An immunohistochemical study of cyclin-dependent kinase 5 (CDK5) expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC): a possible prognostic biomarker. World J Surg Oncol. 2016;14:34. CrossRefPubMedPubMedCentral
Lindqvist J, Imanishi SY, Torvaldson E, Malinen M, Remes M, Orn F, Palvimo JJ, Eriksson JE. 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. Mol Biol Cell. 2015;26:1971–84. CrossRefPubMedPubMedCentral
Charlton P, Spicer J. Targeted therapy in cancer. Medicine. 2016;44:34–8. CrossRef
Nemunaitis JJ, Small KA, Kirschmeier P, Zhang D, Zhu Y, Jou YM, Statkevich P, Yao SL, Bannerji R. A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J Transl Med. 2013;11:259. CrossRefPubMedPubMedCentral
Li R, Liu GZ, Luo SY, Chen R, Zhang JX. Cyclin I promotes cisplatin resistance via Cdk5 activation in cervical cancer. Eur Rev Med Pharmacol Sci. 2015;19:4533–41. PubMed
Zhang S, Lu Z, Mao W, Ahmed AA, Yang H, Zhou J, Jennings N, Rodriguez-Aguayo C, Lopez-Berestein G, Miranda R, et al. CDK5 Regulates Paclitaxel Sensitivity in Ovarian Cancer Cells by Modulating AKT Activation, p21Cip1- and p27Kip1-Mediated G1 Cell Cycle Arrest and Apoptosis. PLoS One. 2015;10:e0131833. CrossRefPubMedPubMedCentral
- Cdk5 links with DNA damage response and cancer
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