Cdk5-mediated inhibition of APC/C-Cdh1 switches on the cyclin D1-Cdk4-pRb pathway causing aberrant S-phase entry of postmitotic neurons

Sci Rep. 2015 Dec 10;5:18180. doi: 10.1038/srep18180.

Abstract

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that regulates cell cycle progression in proliferating cells. To enter the S-phase, APC/C must be inactivated by phosphorylation of its cofactor, Cdh1. In post-mitotic cells such as neurons APC/C-Cdh1 complex is highly active and responsible for the continuous degradation of mitotic cyclins. However, the specific molecular pathway that determines neuronal cell cycle blockade in post-mitotic neurons is unknown. Here, we show that activation of glutamatergic receptors in rat cortical primary neurons endogenously triggers cyclin-dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1 leading to its cytoplasmic accumulation and disassembly from the APC3 core protein, causing APC/C inactivation. Conversely, pharmacological or genetic inhibition of Cdk5 promotes Cdh1 ubiquitination and proteasomal degradation. Furthermore, we show that Cdk5-mediated phosphorylation and inactivation of Cdh1 leads to p27 depletion, which switches on the cyclin D1-cyclin-dependent kinase-4 (Cdk4)-retinoblastoma protein (pRb) pathway to allow the S-phase entry of neurons. However, neurons do not proceed through the cell cycle and die by apoptosis. These results indicate that APC/C-Cdh1 actively suppresses an aberrant cell cycle entry and death of neurons, highlighting its critical function in neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / antagonists & inhibitors
  • Adenomatous Polyposis Coli Protein / metabolism*
  • Animals
  • Antigens, CD
  • Cadherins / metabolism*
  • Caspase 3 / metabolism
  • Cell Cycle
  • Cells, Cultured
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Glutamic Acid
  • Mitosis
  • Neurons / metabolism*
  • Phosphorylation
  • Protein Stability
  • Rats
  • Retinoblastoma Protein / metabolism*
  • S Phase*
  • Signal Transduction*

Substances

  • Adenomatous Polyposis Coli Protein
  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Retinoblastoma Protein
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Glutamic Acid
  • Cyclin-Dependent Kinase 5
  • Caspase 3