Cdk5 May Be an Atypical Kinase, but Not in the Way You Think



Cyclin-dependent kinase 5 (Cdk5) is a non-traditional CDK. It relies on two specific activators––p35 and p39––that are structurally similar to cyclins but genetically distinct. Analysis of the Cdk5 knockout (or the double p35/p39 knockout) has led to the view that the primary function of Cdk5 is in the migration and maturation of embryonic post-mitotic neurons. The literature has no reference to a role of Cdk5 in normal cell cycle regulation. Recent data from our lab, however, suggest that while it may not function as a traditional CDK and facilitate cell cycle progression, it does play a crucial role as a cell cycle suppressor in normal post-mitotic neurons. In this chapter, we review the evidence that this unique function is important for neuronal cell survival and differentiation. The action of Cdk5 in neurons appears to have sub-cellular specificity as well. We present early evidence that it is the nuclear form of Cdk5 that is crucial for holding the cell cycle in check. Cdk5 is found to exit the nucleus in stressed neurons at risk for death. The shift in sub-cellular location is accompanied by cell cycle re-entry and neuronal death. This “new” function of Cdk5 raises cautions in the design of Cdk5-directed drugs for the therapy of neurodegenerative diseases


Cell Cycle Amyotrophic Lateral Sclerosis Focal Adhesion Kinase Cdk5 Activity Cell Cycle Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



All three authors wish to acknowledge support during the writing of this review by grants from the NIH (NS20591 and AG24494).


  1. Ahlijanian MK, Barrezueta NX, Williams RD, Jakowski A, Kowsz KP, McCarthy S, Coskran T, Carlo A, Seymour PA, Burkhardt JE, Nelson RB, McNeish JD (2000) Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc Natl Acad Sci U S A 97:2910–2915.PubMedGoogle Scholar
  2. Akoulitchev S, Chuikov S, Reinberg D (2000) TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407:102–106.PubMedGoogle Scholar
  3. Al-Ubaidi MR, Font RL, Quiambao AB, Keener MJ, Liou GI, Overbeek PA, Baehr W (1992) Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter. J Cell Biol 119:1681–1687.PubMedGoogle Scholar
  4. Al-Ubaidi MR, Mangini NJ, Quiambao AB, Myers KM, Abler AS, Chang CJ, Tso MO, Butel JS, Hollyfield JG (1997) Unscheduled DNA replication precedes apoptosis of photoreceptors expressing SV40 T antigen. Exp Eye Res 64:573–585.PubMedGoogle Scholar
  5. Appert-Collin A, Hugel B, Levy R, Niederhoffer N, Coupin G, Lombard Y, Andre P, Poindron P, Gies JP (2006) Cyclin dependent kinase inhibitors prevent apoptosis of postmitotic mouse motoneurons. Life Sci 79:484–490.PubMedGoogle Scholar
  6. Bian F, Nath R, Sobocinski G, Booher RN, Lipinski WJ, Callahan MJ, Pack A, Wang KK, Walker LC (2002) Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice. J Comp Neurol 446:257–266.Google Scholar
  7. Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC, Jr., Nairn AC, Greengard P (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402:669–671.PubMedGoogle Scholar
  8. Bloom J, Cross FR (2007) Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol Cell Biol 8:149–160.PubMedGoogle Scholar
  9. Busser J, Geldmacher DS, Herrup K (1998) Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J Neurosci 18:2801–2807.PubMedGoogle Scholar
  10. Chen P, Zindy F, Abdala C, Liu F, Li X, Roussel MF, Segil N (2003) Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nat Cell Biol 5:422–426.PubMedGoogle Scholar
  11. Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ (1999) The p21(Cip1) and p27(Kip1) CDK ‘inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 18:1571–1583.PubMedGoogle Scholar
  12. Chergui K, Svenningsson P, Greengard P (2004) Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. Proc Natl Acad Sci U S A 101:2191–2196.PubMedGoogle Scholar
  13. Cicero S, Herrup K (2005) Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J Neurosci 25:9658–9668.PubMedGoogle Scholar
  14. Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, Berns A, te Riele H (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359:328–330.PubMedGoogle Scholar
  15. Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471–483.PubMedGoogle Scholar
  16. Desai D, Wessling HC, Fisher RP, Morgan DO (1995) Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2. Mol Cell Biol 15:345–350.PubMedGoogle Scholar
  17. Dinarina A, Perez LH, Davila A, Schwab M, Hunt T, Nebreda AR (2005) Characterization of a new family of cyclin-dependent kinase activators. Biochem J 386:349–355.PubMedGoogle Scholar
  18. Ding XL, Husseman J, Tomashevski A, Nochlin D, Jin LW, Vincent I (2000) The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer's disease. Am J Pathol 157:1983–1990.PubMedGoogle Scholar
  19. Farinelli SE, Park DS, Greene LA (1996) Nitric oxide delays the death of trophic factor-deprived PC12 cells and sympathetic neurons by a cGMP-mediated mechanism. J Neurosci 16:2325–2334.PubMedGoogle Scholar
  20. Feddersen RM, Clark HB, Yunis WS, Orr HT (1995) In vivo viability of postmitotic Purkinje neurons requires pRb family member function. Mol Cell Neurosci 6:153–167.PubMedGoogle Scholar
  21. Feddersen RM, Ehlenfeldt R, Yunis WS, Clark HB, Orr HT (1992) Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice. Neuron 9:955–966.PubMedGoogle Scholar
  22. Fu AK, Fu WY, Cheung J, Tsim KW, Ip FC, Wang JH, Ip NY (2001) Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat Neurosci 4:374–381.PubMedGoogle Scholar
  23. Fu WY, Fu AK, Lok KC, Ip FC, Ip NY (2002) Induction of Cdk5 activity in rat skeletal muscle after nerve injury. Neuroreport 13:243–247.PubMedGoogle Scholar
  24. Fu X, Choi YK, Qu D, Yu Y, Cheung NS, Qi RZ (2006) Identification of nuclear import mechanisms for the neuronal Cdk5 activator. J Biol Chem 281(51):39017–39021.Google Scholar
  25. Giese KP, Ris L, Plattner F (2005) Is there a role of the cyclin-dependent kinase 5 activator p25 in Alzheimer's disease? Neuroreport 16:1725–1730.PubMedGoogle Scholar
  26. Gilmore EC, Herrup K (2001) Neocortical cell migration: GABAergic neurons and cells in layers I and VI move in a cyclin-dependent kinase 5-independent manner. J Neurosci 21:9690–9700.PubMedGoogle Scholar
  27. Gilmore EC, Ohshima T, Goffinet AM, Kulkarni AB, Herrup K (1998) Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex. J Neurosci 18:6370–6377.PubMedGoogle Scholar
  28. Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS (1999) Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F x DP, in B-amyloid-induced neuronal death. J Biol Chem 274:19011–19016.PubMedGoogle Scholar
  29. Grynspan F, Griffin WR, Cataldo A, Katayama S, Nixon RA (1997) Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer's disease. Brain Res 763:145–158.PubMedGoogle Scholar
  30. Hallows JL, Chen K, DePinho RA, Vincent I (2003) Decreased cyclin-dependent kinase 5 (cdk5) activity is accompanied by redistribution of cdk5 and cytoskeletal proteins and increased cytoskeletal protein phosphorylation in p35 null mice. J Neurosci 23:10633–10644.PubMedGoogle Scholar
  31. Hallows JL, Iosif RE, Biasell RD, Vincent I (2006) p35/p25 is not essential for tau and cytoskeletal pathology or neuronal loss in Niemann-Pick type C disease. J Neurosci 26:2738–2744.PubMedGoogle Scholar
  32. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805–816.PubMedGoogle Scholar
  33. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, Dobrowolski S, Bai C, Connell-Crowley L, Swindell E, et al. (1995) Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 6:387–400.PubMedGoogle Scholar
  34. Hayashi T, Warita H, Abe K, Itoyama Y (1999) Expression of cyclin-dependent kinase 5 and its activator p35 in rat brain after middle cerebral artery occlusion. Neurosci Lett 265:37–40.PubMedGoogle Scholar
  35. Herrup K, Busser JC (1995) The induction of multiple cell cycle events precedes target-related neuronal death. Development 121:2385–2395.PubMedGoogle Scholar
  36. Herrup K, Yang Y (2007) Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 8:368–378.PubMedGoogle Scholar
  37. Höglinger G, et al. (2007) The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. Proc Natl Acad Sci U S A 104, 3585–3590.PubMedGoogle Scholar
  38. Humbert S, Lanier LM, Tsai LH (2000a) Synaptic localization of p39, a neuronal activator of cdk5. Neuroreport 11:2213–2216.Google Scholar
  39. Humbert S, Dhavan R, Tsai L (2000b) p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton. J Cell Sci 113(Pt 6):975–983.Google Scholar
  40. Husseman JW, Nochlin D, Vincent I (2000) Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol Aging 21:815–828.PubMedGoogle Scholar
  41. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse. Nature 359:295–300.PubMedGoogle Scholar
  42. Kaldis P (2007) Another piece of the p27Kip1 puzzle. Cell 128:241–244.PubMedGoogle Scholar
  43. Kasten M, Giordano A (2001) Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 20:1832–1838.PubMedGoogle Scholar
  44. Kawauchi T, Chihama K, Nabeshima Y, Hoshino M (2006) Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol 8:17–26.PubMedGoogle Scholar
  45. Ko J, Humbert S, Bronson RT, Takahashi S, Kulkarni AB, Li E, Tsai LH (2001) p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J Neurosci 21:6758–6771.PubMedGoogle Scholar
  46. Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:288–294.PubMedGoogle Scholar
  47. Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364.PubMedGoogle Scholar
  48. Lees E (1995) Cyclin dependent kinase regulation. Curr Opin Cell Biol 7:773–780.PubMedGoogle Scholar
  49. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331.PubMedGoogle Scholar
  50. Lew J, Beaudette K, Litwin CM, Wang JH (1992) Purification and characterization of a novel proline-directed protein kinase from bovine brain. J Biol Chem 267:13383–13390.PubMedGoogle Scholar
  51. Lew J, Huang QQ, Qi Z, Winkfein RJ, Aebersold R, Hunt T, Wang JH (1994) A brain-specific activator of cyclin-dependent kinase 5. Nature 371:423–426.PubMedGoogle Scholar
  52. Love S (2003) Neuronal expression of cell cycle-related proteins after brain ischaemia in man. Neurosci Lett 353:29–32.PubMedGoogle Scholar
  53. Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30:630–641.PubMedGoogle Scholar
  54. Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ (1995) p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev 9:650–662.PubMedGoogle Scholar
  55. Matsushita M, Tomizawa K, Lu YF, Moriwaki A, Tokuda M, Itano T, Wang JH, Hatase O, Matsui H (1996) Distinct cellular compartment of cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activator protein (p35nck5a) in the developing rat cerebellum. Brain Res 734:319–322.PubMedGoogle Scholar
  56. Matsuura I, Wang JH (1996) Demonstration of cyclin-dependent kinase inhibitory serine/threonine kinase in bovine thymus. J Biol Chem 271:5443–5450.PubMedGoogle Scholar
  57. McShea A, Lee HG, Petersen RB, Casadesus G, Vincent I, Linford NJ, Funk JO, Shapiro RA, Smith MA (2007) Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta 1772:467–472.PubMedGoogle Scholar
  58. Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH (1992) A family of human cdc2-related protein kinases. EMBO J 11:2909–2917.PubMedGoogle Scholar
  59. Miyajima M, Nornes HO, Neuman T (1995) Cyclin E is expressed in neurons and forms complexes with cdk5. Neuroreport 6:1130–1132.PubMedGoogle Scholar
  60. Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291.PubMedGoogle Scholar
  61. Moy LY, Tsai LH (2004) Cyclin-dependent kinase 5 phosphorylates serine 31 of tyrosine hydroxylase and regulates its stability. J Biol Chem 279:54487–54493.PubMedGoogle Scholar
  62. Nagy Z, Esiri MM, Cato AM, Smith AD (1997) Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol (Berl) 94:6–15.Google Scholar
  63. Nath R, Davis M, Probert AW, Kupina NC, Ren X, Schielke GP, Wang KK (2000) Processing of cdk5 activator p35 to its truncated form (p25) by calpain in acutely injured neuronal cells. Biochem Biophys Res Commun 274:16–21.PubMedGoogle Scholar
  64. Neystat M, Rzhetskaya M, Oo TF, Kholodilov N, Yarygina O, Wilson A, El-Khodor BF, Burke RE (2001) Expression of cyclin-dependent kinase 5 and its activator p35 in models of induced apoptotic death in neurons of the substantia nigra in vivo. J Neurochem 77:1611–1625.PubMedGoogle Scholar
  65. Nguyen MD, Julien JP (2003) Cyclin-dependent kinase 5 in amyotrophic lateral sclerosis. Neurosignals 12:215–220.PubMedGoogle Scholar
  66. Nguyen MD, Lariviere RC, Julien JP (2001) Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron 30:135–147.PubMedGoogle Scholar
  67. Nguyen MD, Boudreau M, Kriz J, Couillard-Despres S, Kaplan DR, Julien JP (2003) Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci 23:2131–2140.PubMedGoogle Scholar
  68. Niethammer M, Smith DS, Ayala R, Peng J, Ko J, Lee MS, Morabito M, Tsai LH (2000) NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 28:697–711.PubMedGoogle Scholar
  69. Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J, Gaynor K, LaFrancois J, Wang L, Kondo T, Davies P, Burns M, Veeranna, Nixon R, Dickson D, Matsuoka Y, Ahlijanian M, Lau LF, Duff K (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38:555–565.Google Scholar
  70. Ohshima T, Gilmore EC, Longenecker G, Jacobowitz DM, Brady RO, Herrup K, Kulkarni AB (1999) Migration defects of cdk5(–/–) neurons in the developing cerebellum is cell autonomous. J Neurosci 19:6017–6026.PubMedGoogle Scholar
  71. Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci U S A 93:11173–11178.Google Scholar
  72. Park DS, Farinelli SE, Greene LA (1996) Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. J Biol Chem 271:8161–8169.PubMedGoogle Scholar
  73. Park KH, Hallows JL, Chakrabarty P, Davies P, Vincent I (2007) Conditional neuronal simian virus 40 T antigen expression induces Alzheimer-like tau and amyloid pathology in mice. J Neurosci 27:2969–2978.PubMedGoogle Scholar
  74. Park DS, Levine B, Ferrari G, Greene LA (1997a) Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. J Neurosci 17:8975–8983.Google Scholar
  75. Park DS, Morris EJ, Greene LA, Geller HM (1997b) G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. J Neurosci 17:1256–1270.Google Scholar
  76. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622.PubMedGoogle Scholar
  77. Patzke H, Tsai LH (2002) Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29. J Biol Chem 277:8054–8060.PubMedGoogle Scholar
  78. Plattner F, Angelo M, Giese KP (2006) The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J Biol Chem 281:25457–25465.PubMedGoogle Scholar
  79. Poon RY, Lew J, Hunter T (1997) Identification of functional domains in the neuronal Cdk5 activator protein. J Biol Chem 272:5703–5708.PubMedGoogle Scholar
  80. Ranganathan S, Bowser R (2003) Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Am J Pathol 162:823–835.PubMedGoogle Scholar
  81. Rashidian J, Iyirhiaro G, Aleyasin H, Rios M, Vincent I, Callaghan S, Bland RJ, Slack RS, During MJ, Park DS (2005) Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Proc Natl Acad Sci U S A 102:14080–14085.PubMedGoogle Scholar
  82. Ren S, Rollins BJ (2004) Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 117:239–251.PubMedGoogle Scholar
  83. Russo AA, Jeffrey PD, Pavletich NP (1996) Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol 3:696–700.PubMedGoogle Scholar
  84. Sahlgren CM, Mikhailov A, Vaittinen S, Pallari HM, Kalimo H, Pant HC, Eriksson JE (2003) Cdk5 regulates the organization of Nestin and its association with p35. Mol Cell Biol 23:5090–5106.PubMedGoogle Scholar
  85. Sano M, Schneider MD (2003) Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size. Cell Cycle 2:99–104.PubMedGoogle Scholar
  86. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512.PubMedGoogle Scholar
  87. Shuttleworth J (1995) The regulation and functions of cdk7. Prog Cell Cycle Res 1:229–240.PubMedGoogle Scholar
  88. Tan TC, Valova VA, Malladi CS, Graham ME, Berven LA, Jupp OJ, Hansra G, McClure SJ, Sarcevic B, Boadle RA, Larsen MR, Cousin MA, Robinson PJ (2003) Cdk5 is essential for synaptic vesicle endocytosis. Nat Cell Biol 5:701–710.PubMedGoogle Scholar
  89. Tanaka T, Serneo FF, Tseng HC, Kulkarni AB, Tsai LH, Gleeson JG (2004) Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration. Neuron 41:215–227.PubMedGoogle Scholar
  90. Tandon A, Yu H, Wang L, Rogaeva E, Sato C, Chishti MA, Kawarai T, Hasegawa H, Chen F, Davies P, Fraser PE, Westaway D, St George-Hyslop PH (2003) Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles. J Neurochem 86:572–581.PubMedGoogle Scholar
  91. Tang D, Yeung J, Lee KY, Matsushita M, Matsui H, Tomizawa K, Hatase O, Wang JH (1995) An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem 270:26897–26903.PubMedGoogle Scholar
  92. Tarricone C, Dhavan R, Peng J, Areces LB, Tsai LH, Musacchio A (2001) Structure and regulation of the CDK5-p25(nck5a) complex. Mol Cell 8:657–669.PubMedGoogle Scholar
  93. Tomizawa K, Ohta J, Matsushita M, Moriwaki A, Li ST, Takei K, Matsui H (2002) Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity. J Neurosci 22:2590–2597.PubMedGoogle Scholar
  94. Tsai LH, Delalle I, Caviness VS, Jr., Chae T, Harlow E (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371:419–423.PubMedGoogle Scholar
  95. Van den Haute C, Spittaels K, Van Dorpe J, Lasrado R, Vandezande K, Laenen I, Geerts H, Van Leuven F (2001) Coexpression of human cdk5 and its activator p35 with human protein tau in neurons in brain of triple transgenic mice. Neurobiol Dis 8:32–44.PubMedGoogle Scholar
  96. van den Heuvel S, Harlow E (1993) Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262:2050–2054.PubMedGoogle Scholar
  97. Vincent I, Bu B, Hudson K, Husseman J, Nochlin D, Jin L (2001) Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer's disease. Neuroscience 105:639–650.PubMedGoogle Scholar
  98. Vincent I, Jicha G, Rosado M, Dickson DW (1997) Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci 17:3588–3598.PubMedGoogle Scholar
  99. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310.PubMedGoogle Scholar
  100. Wang J, Liu S, Fu Y, Wang JH, Lu Y (2003) Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci 6:1039–1047.PubMedGoogle Scholar
  101. Wen Y, Yang S, Liu R, Simpkins JW (2005) Cell-cycle regulators are involved in transient cerebral ischemia induced neuronal apoptosis in female rats. FEBS Lett 579:4591–4599.PubMedGoogle Scholar
  102. Xie Z, Sanada K, Samuels BA, Shih H, Tsai LH (2003) Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Cell 114:469–482.PubMedGoogle Scholar
  103. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704.PubMedGoogle Scholar
  104. Xiong Y, Zhang H, Beach D (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71:505–514.PubMedGoogle Scholar
  105. Yang Y, Herrup K (2005) Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci 25:2522–2529.PubMedGoogle Scholar
  106. Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci 21:2661–2668.PubMedGoogle Scholar
  107. Yang Y, Mufson EJ, Herrup K (2003) Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J Neurosci 23:2557–2563.PubMedGoogle Scholar
  108. Yang Y, Varvel NH, Lamb BT, Herrup K (2006) Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models. J Neurosci 26:775–784.PubMedGoogle Scholar
  109. Zhang Q, Ahuja HS, Zakeri ZF, Wolgemuth DJ (1997) Cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. Dev Biol 183:222–233.PubMedGoogle Scholar
  110. Zhang J, Krishnamurthy PK, Johnson GV (2002) Cdk5 phosphorylates p53 and regulates its activity. J Neurochem 81:307–313.PubMedGoogle Scholar
  111. Zhang H, Xiong Y, Beach D (1993) Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. Mol Biol Cell 4:897–906.PubMedGoogle Scholar
  112. Zhu Y, Lin L, Kim S, Quaglino D, Lockshin RA, Zakeri Z (2002) Cyclin dependent kinase 5 and its interacting proteins in cell death induced in vivo by cyclophosphamide in developing mouse embryos. Cell Death Differ 9:421–430.PubMedGoogle Scholar
  113. Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu CL, Lanier LM, Gertler FB, Vidal M, Van Etten RA, Tsai LH (2000) Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26:633–646.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Cell Biology and NeuroscienceNelson Biological Laboratories, Rutgers UniversityPiscatawayUSA

Personalised recommendations