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Gene Review

CDK5R1  -  cyclin-dependent kinase 5, regulatory...

Homo sapiens

Synonyms: CDK5 activator 1, CDK5P35, CDK5R, Cyclin-dependent kinase 5 activator 1, Cyclin-dependent kinase 5 regulatory subunit 1, ...
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Disease relevance of CDK5R1


Psychiatry related information on CDK5R1


High impact information on CDK5R1

  • Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease [7].
  • Consequently, the p25/cdk5 kinase hyperphosphorylates tau, disrupts the cytoskeleton and promotes the death (apoptosis) of primary neurons [7].
  • Cyclin-dependent kinase 5 (cdk5) and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination [7].
  • Finally, we provide evidence that the CDK5-p25 complex employs a distinct mechanism from the phospho-CDK2-cyclin A complex to establish substrate specificity [8].
  • The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin [9].

Chemical compound and disease context of CDK5R1


Biological context of CDK5R1


Anatomical context of CDK5R1


Associations of CDK5R1 with chemical compounds


Physical interactions of CDK5R1

  • In turn, the p25/Cdk5 complex aberrantly phosphorylates its substrates tau and neurofilaments, which has been implicated in the pathogenesis of these disorders [23].

Enzymatic interactions of CDK5R1

  • Although the kinase activity of CDK5 in phosphorylating tau was significantly higher in the presence of p25, the affinity of CDK5 for tau was not different [15].

Co-localisations of CDK5R1


Regulatory relationships of CDK5R1

  • These results suggest that cleavage of p35 to p25 greatly enhances the kinase activity of CDK5 and increases the phosphorylation of Ser(202)/Thr(205) [15].
  • IFN-gamma enhanced the LPS-induced accumulation of p40 mRNA and directly induced a several-fold increase in the accumulation of p35 mRNA [25].
  • This aberrant response leading to neurofibrillary degeneration may be triggered by the sequential combination of three partners: the complex Cdk5/p25 induces both apoptosis and the "abnormal mitotic Tau phosphorylation". These mitotic epitopes may allow for the nuclear depletion of Pin1 [26].

Other interactions of CDK5R1

  • The isoform, designated the neuronal Cdk5 activator isoform (p39nck5ai), showed a high degree of sequence similarity to p35nck5a with 57% amino acid identity [18].
  • Neurite elongation by FK506 (10 nM), determined by measuring neurite lengths at 96 and 168 h, was completely blocked by the mitogen-activated protein kinase inhibitor PD 098059 (10 microM) and prevented, in a concentration-dependent fashion, by the p23 antibody [20].
  • The implications of p25/Cdk5 in neurotoxicity, beta-amyloid plaque and neurofibrillary tangle pathology will be discussed [27].
  • Our data show that in 1,25D(3)-treated cells, p35 and Egr1 protein levels are elevated in a dose-dependent manner at the onset of the late stage of differentiation [14].
  • Prediction of mRNA and protein secondary structures revealed that two changes lead to putative structural alterations in the mutated c.2254C>G CDK5R1 3'UTR and in OMG T408A gene product [5].

Analytical, diagnostic and therapeutic context of CDK5R1


  1. Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles. Tandon, A., Yu, H., Wang, L., Rogaeva, E., Sato, C., Chishti, M.A., Kawarai, T., Hasegawa, H., Chen, F., Davies, P., Fraser, P.E., Westaway, D., St George-Hyslop, P.H. J. Neurochem. (2003) [Pubmed]
  2. Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. Lin, H., Juang, J.L., Wang, P.S. J. Biol. Chem. (2004) [Pubmed]
  3. p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death. Hamdane, M., Bretteville, A., Sambo, A.V., Schindowski, K., Bégard, S., Delacourte, A., Bertrand, P., Buée, L. J. Cell. Sci. (2005) [Pubmed]
  4. Bordetella pertussis inhibition of interleukin-12 (IL-12) p70 in human monocyte-derived dendritic cells blocks IL-12 p35 through adenylate cyclase toxin-dependent cyclic AMP induction. Spensieri, F., Fedele, G., Fazio, C., Nasso, M., Stefanelli, P., Mastrantonio, P., Ausiello, C.M. Infect. Immun. (2006) [Pubmed]
  5. Mutations and novel polymorphisms in coding regions and UTRs of CDK5R1 and OMG genes in patients with non-syndromic mental retardation. Venturin, M., Moncini, S., Villa, V., Russo, S., Bonati, M.T., Larizza, L., Riva, P. Neurogenetics (2006) [Pubmed]
  6. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Patrick, G.N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., Tsai, L.H. Nature (1999) [Pubmed]
  7. Neurotoxicity induces cleavage of p35 to p25 by calpain. Lee, M.S., Kwon, Y.T., Li, M., Peng, J., Friedlander, R.M., Tsai, L.H. Nature (2000) [Pubmed]
  8. Structure and regulation of the CDK5-p25(nck5a) complex. Tarricone, C., Dhavan, R., Peng, J., Areces, L.B., Tsai, L.H., Musacchio, A. Mol. Cell (2001) [Pubmed]
  9. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. Lee, E., Trepicchio, W.L., Oestreicher, J.L., Pittman, D., Wang, F., Chamian, F., Dhodapkar, M., Krueger, J.G. J. Exp. Med. (2004) [Pubmed]
  10. Inhibition of the cdk5/p25 fragment formation may explain the antiapoptotic effects of melatonin in an experimental model of Parkinson's disease. Alvira, D., Tajes, M., Verdaguer, E., Acuña-Castroviejo, D., Folch, J., Camins, A., Pallas, M. J. Pineal Res. (2006) [Pubmed]
  11. Molecular cloning and mRNA expression of porcine interleukin-12. Foss, D.L., Murtaugh, M.P. Vet. Immunol. Immunopathol. (1997) [Pubmed]
  12. Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease. Helal, C.J., Sanner, M.A., Cooper, C.B., Gant, T., Adam, M., Lucas, J.C., Kang, Z., Kupchinsky, S., Ahlijanian, M.K., Tate, B., Menniti, F.S., Kelly, K., Peterson, M. Bioorg. Med. Chem. Lett. (2004) [Pubmed]
  13. Production and characterization of human monoclonal antibodies against core protein p25 and transmembrane glycoprotein gp41 of HIV-1. Prigent, S., Goossens, D., Clerget-Raslain, B., Bahraoui, E., Roussel, M., Tsikas, G., Laurent, A., Montagnier, L., Salmon, C., Gluckman, J.C. AIDS (1990) [Pubmed]
  14. Up-regulation of Egr1 by 1,25-dihydroxyvitamin D3 contributes to increased expression of p35 activator of cyclin-dependent kinase 5 and consequent onset of the terminal phase of HL60 cell differentiation. Chen, F., Wang, Q., Wang, X., Studzinski, G.P. Cancer Res. (2004) [Pubmed]
  15. Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau. Hashiguchi, M., Saito, T., Hisanaga, S., Hashiguchi, T. J. Biol. Chem. (2002) [Pubmed]
  16. Identification of a common protein association region in the neuronal Cdk5 activator. Wang, X., Ching, Y.P., Lam, W.H., Qi, Z., Zhang, M., Wang, J.H. J. Biol. Chem. (2000) [Pubmed]
  17. Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor. Ching, Y.P., Pang, A.S., Lam, W.H., Qi, R.Z., Wang, J.H. J. Biol. Chem. (2002) [Pubmed]
  18. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. Tang, D., Yeung, J., Lee, K.Y., Matsushita, M., Matsui, H., Tomizawa, K., Hatase, O., Wang, J.H. J. Biol. Chem. (1995) [Pubmed]
  19. A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells. Zheng, Y.L., Li, B.S., Amin, N.D., Albers, W., Pant, H.C. Eur. J. Biochem. (2002) [Pubmed]
  20. FK506 requires stimulation of the extracellular signal-regulated kinase 1/2 and the steroid receptor chaperone protein p23 for neurite elongation. Gold, B.G., Zhong, Y.P. Neurosignals (2004) [Pubmed]
  21. Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25 and CDK2/cyclin A dynamics. Otyepka, M., Bártová, I., Kríz, Z., Koca, J. J. Biol. Chem. (2006) [Pubmed]
  22. Glutamate treatment and p25 transfection increase Cdk5 mediated tau phosphorylation in SH-SY5Y cells. Jämsä, A., Bäckström, A., Gustafsson, E., Dehvari, N., Hiller, G., Cowburn, R.F., Vasänge, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  23. Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. Kesavapany, S., Li, B.S., Amin, N., Zheng, Y.L., Grant, P., Pant, H.C. Biochim. Biophys. Acta (2004) [Pubmed]
  24. p35nck5a and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains with Parkinson's disease. Nakamura, S., Kawamoto, Y., Nakano, S., Akiguchi, I., Kimura, J. Acta Neuropathol. (1997) [Pubmed]
  25. Interleukin-12 production by human polymorphonuclear leukocytes. Cassatella, M.A., Meda, L., Gasperini, S., D'Andrea, A., Ma, X., Trinchieri, G. Eur. J. Immunol. (1995) [Pubmed]
  26. Neurofibrillary degeneration of the Alzheimer-type: an alternate pathway to neuronal apoptosis? Hamdane, M., Delobel, P., Sambo, A.V., Smet, C., Bégard, S., Violleau, A., Landrieu, I., Delacourte, A., Lippens, G., Flament, S., Buée, L. Biochem. Pharmacol. (2003) [Pubmed]
  27. Cdk5, a therapeutic target for Alzheimer's disease? Tsai, L.H., Lee, M.S., Cruz, J. Biochim. Biophys. Acta (2004) [Pubmed]
  28. A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains. Tseng, H.C., Zhou, Y., Shen, Y., Tsai, L.H. FEBS Lett. (2002) [Pubmed]
  29. Mitotic-like tau phosphorylation by p25-Cdk5 kinase complex. Hamdane, M., Sambo, A.V., Delobel, P., Bégard, S., Violleau, A., Delacourte, A., Bertrand, P., Benavides, J., Buée, L. J. Biol. Chem. (2003) [Pubmed]
  30. Deregulation of cdk5 in Hippocampal sclerosis. Sen, A., Thom, M., Martinian, L., Jacobs, T., Nikolic, M., Sisodiya, S.M. J. Neuropathol. Exp. Neurol. (2006) [Pubmed]
  31. A model of the complex between cyclin-dependent kinase 5 and the activation domain of neuronal Cdk5 activator. Chou, K.C., Watenpaugh, K.D., Heinrikson, R.L. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  32. Cdk5 as a drug target for the treatment of Alzheimer's disease. Lau, L.F., Seymour, P.A., Sanner, M.A., Schachter, J.B. J. Mol. Neurosci. (2002) [Pubmed]
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