Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex.
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.
Zhang
Jie
J
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Li
Huifang
H
Yabut
Odessa
O
Fitzpatrick
Haley
H
D'Arcangelo
Gabriella
G
Herrup
Karl
K
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*
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
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