title: Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex.
abstract: Neurons that reenter a cell cycle after maturation are at increased risk for death, yet the mechanisms by which a normal neuron suppresses the cycle remain mostly unknown. Our laboratory has shown that cyclin-dependent kinase 5 (Cdk5) is a potent cell cycle suppressor, and we report here on the molecular basis of this activity. Cell cycle suppression by Cdk5 requires its binding to the p35 activator protein. The related p39 and p25 proteins cannot serve as substitutes. Unexpectedly, Cdk5 enzymatic activity is not required to perform this function. Rather, the link to cell cycle regulation is made through the formation of a previously unknown complex consisting of the p35-Cdk5 dimer and E2F1. Formation of this complex excludes the E2F1 cofactor, DP1, thus inhibiting E2F1 binding to the promoters of various cell cycle genes. This anti-cell cycle activity is most likely a neuroprotective function of Cdk5.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Huifang
authors.initials: H
authors.lastname: Li
authors.forename: Odessa
authors.initials: O
authors.lastname: Yabut
authors.forename: Haley
authors.initials: H
authors.lastname: Fitzpatrick
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Arcangelo
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000502:physiology; D004247:DNA / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D010770:Phosphotransferases / Q000378:metabolism*; D050680:Transcription Factor DP1 / Q000378:metabolism*
chemical_list: C492236:Cdk5r1 protein, mouse; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D009419:Nerve Tissue Proteins; C493736:Tfdp1 protein, mouse; D050680:Transcription Factor DP1; D004247:DNA; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse
references.citation: Nature. 1992 Jan 9;355(6356):176-9
references.pmid: 1530885
references.citation: J Biol Chem. 1999 Jul 30;274(31):22013-8
references.pmid: 10419526
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3259-63
references.pmid: 8622924
references.citation: Cell. 1991 Jun 28;65(7):1243-53
references.pmid: 1829647
references.citation: Nature. 1999 Dec 9;402(6762):615-22
references.pmid: 10604467
references.citation: Mol Cell Biol. 2007 Jul;27(13):4626-40
references.pmid: 17452458
references.citation: Curr Med Chem. 2008;15(23):2321-8
references.pmid: 18855662
references.citation: Genes Dev. 2001 Feb 1;15(3):267-85
references.pmid: 11159908
references.citation: Mol Cell. 2002 Apr;9(4):789-98
references.pmid: 11983170
references.citation: J Neurosci. 2007 Nov 14;27(46):12555-64
references.pmid: 18003834
references.citation: Cell. 1996 May 17;85(4):549-61
references.pmid: 8653790
references.citation: Cell. 1992 Oct 30;71(3):505-14
references.pmid: 1358458
references.citation: Mol Cell Biol. 2001 Jul;21(14):4684-99
references.pmid: 11416145
references.citation: Neuron. 2003 Apr 10;38(1):33-46
references.pmid: 12691662
references.citation: Dev Biol. 2001 Dec 1;240(1):237-46
references.pmid: 11784059
references.citation: Nature. 1998 Sep 10;395(6698):194-8
references.pmid: 9744280
references.citation: Drug News Perspect. 2006 Oct;19(8):453-60
references.pmid: 17160145
references.citation: Mol Biol Cell. 1993 Sep;4(9):897-906
references.pmid: 7903056
references.citation: Mol Cell. 2001 Sep;8(3):657-69
references.pmid: 11583627
references.citation: Neuron. 2008 Dec 10;60(5):803-17
references.pmid: 19081376
references.citation: EMBO J. 1993 Nov;12(11):4317-24
references.pmid: 8223441
references.citation: J Biol Chem. 2005 Jul 1;280(26):24642-8
references.pmid: 15863509
references.citation: J Biol Chem. 2005 Jan 14;280(2):1095-102
references.pmid: 15528185
references.citation: J Neurochem. 1998 Jan;70(1):335-40
references.pmid: 9422379
references.citation: Cell. 1994 Jul 15;78(1):161-72
references.pmid: 8033208
references.citation: J Biol Chem. 2002 Mar 1;277(9):7324-32
references.pmid: 11741927
references.citation: J Neurosci. 2006 Jan 18;26(3):775-84
references.pmid: 16421297
references.citation: Science. 1993 Dec 24;262(5142):2050-4
references.pmid: 8266103
references.citation: Nat Rev Mol Cell Biol. 2006 Jun;7(6):449-56
references.pmid: 16625152
references.citation: Curr Opin Neurobiol. 2004 Jun;14(3):390-4
references.pmid: 15194121
references.citation: Genes Dev. 1996 Apr 1;10(7):816-25
references.pmid: 8846918
references.citation: J Neurosci. 2003 Apr 1;23(7):2557-63
references.pmid: 12684440
references.citation: J Biol Chem. 2006 Dec 22;281(51):39014-21
references.pmid: 17060323
references.citation: Nat Biotechnol. 2003 May;21(5):539-45
references.pmid: 12692560
references.citation: Nature. 1994 Sep 29;371(6496):419-23
references.pmid: 8090221
references.citation: Genes Dev. 2002 Jan 15;16(2):245-56
references.pmid: 11799067
references.citation: Nat Rev Neurosci. 2007 May;8(5):368-78
references.pmid: 17453017
references.citation: Biotechnol J. 2007 Aug;2(8):949-57
references.pmid: 17526057
references.citation: J Cell Biol. 2001 Apr 2;153(1):121-36
references.pmid: 11285279
references.citation: EMBO J. 1992 Aug;11(8):2909-17
references.pmid: 1639063
references.citation: J Neurosci. 2008 Aug 27;28(35):8747-55
references.pmid: 18753376
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8772-7
references.pmid: 18550843
references.citation: Biotechnol J. 2007 Aug;2(8):941-8
references.pmid: 17597494
references.citation: J Neurosci. 2005 Oct 19;25(42):9658-68
references.pmid: 16237170
references.citation: J Neurosci. 1998 Aug 15;18(16):6370-7
references.pmid: 9698328
references.citation: Nat Rev Mol Cell Biol. 2002 Jan;3(1):11-20
references.pmid: 11823794
references.citation: J Neurosci. 2001 Sep 1;21(17):6758-71
references.pmid: 11517264