Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo.
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.
Rashidian
Juliet
J
Ottawa Health Research Institute, Neuroscience Group, Ottawa, ON, Canada K1H 8M5.
Iyirhiaro
Grace
G
Aleyasin
Hossein
H
Rios
Mario
M
Vincent
Inez
I
Callaghan
Steven
S
Bland
Ross J
RJ
Slack
Ruth S
RS
During
Matthew J
MJ
Park
David S
DS
D000818:Animals; D016923:Cell Death; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D020521:Stroke / Q000201:enzymology / Q000473:pathology
D009419:Nerve Tissue Proteins; D016160:Retinoblastoma Protein; C089495:neuronal Cdk5 activator (p25-p35); D019938:Cyclin D1