Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo

Juliet Rashidian, Grace Iyirhiaro, Hossein Aleyasin, Mario Rios, Inez Vincent, Steven Callaghan, Ross J. Bland, Ruth S. Slack, Matthew J. During, David S. Park

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

The mechanisms involving neuronal death after ischemic/hypoxic insult are complex, involving both rapid (excitotoxic) and delayed (apoptotic-like) processes. Recent evidence suggests that cell cycle regulators such as cyclin-dependent kinases are abnormally activated in neuropathological conditions, including stroke. However, the function of this activation is unclear. Here, we provide evidence that inhibition of the cell cycle regulator, Cdk4, and its activator, cyclinD1, plays critical roles in the delayed death component of ischemic/hypoxic stress by regulating the tumor suppressor retinoblastoma protein. In contrast, the excitotoxic component of ischemia hypoxia is predominately regulated by Cdk5 and its activator p35, components of a cyclin-dependent kinase complex associated with neuronal development. Hence, our data both characterize the functional significance of the cell cycle Cdk4 and neuronal Cdk5 signals as well as define the pathways and circumstances by which they act to control ischemic/hypoxic damage.

Original languageEnglish
Pages (from-to)14080-14085
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number39
DOIs
StatePublished - 27 Sep 2005
Externally publishedYes

Keywords

  • Hypoxia
  • Stroke

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