tailieunhanh - Báo cáo khoa học: A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells

Cyclin-dependent kinase-5 (Cdk5) is a serine/threonine kinase activated by its neuron-specific activator, p35, or its truncated form, p25. It has been proposed that the deregu-lation of Cdk5 activity by association with p25 in human brain tissue disrupts the neuronal cytoskeleton and may be involved in neurodegenerative diseases such as Alzheimer’s disease. In this study, we demonstrate that a short peptide (amino acid residues 154–279; Cdk5 inhibitory peptide; CIP), derived from p35, specifically inhibits Cdk5 activity in vitro and in HEK293 cells cotransfected with the peptide and Cdk5/p25, but had no effect on endogenous cdc2 kinase activity | Eur. J. Biochem. 269 4427-4434 2002 FEBS 2002 doi A peptide derived from cyclin-dependent kinase activator p35 specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells Ya-li Zheng Bing-Sheng Li Niranjana D. Amin Wayne Albers and Harish C. Pant Laboratory of Neurochemistry National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda USA Cyclin-dependent kinase-5 Cdk5 is a serine threonine kinase activated by its neuron-specific activator p35 or its truncated form p25. It has been proposed that the deregulation of Cdk5 activity by association with p25 in human brain tissue disrupts the neuronal cytoskeleton and may be involved in neurodegenerative diseases such as Alzheimer s disease. In this study we demonstrate that a short peptide amino acid residues 154-279 Cdk5 inhibitory peptide CIP derived from p35 specifically inhibits Cdk5 activity in vitro and in HEK293 cells cotransfected with the peptide and Cdk5 p25 but had no effect on endogenous cdc2 kinase activity. Moreover we demonstrate that the phosphorylation of tau in HEK293 cells cotransfected with Cdk5 p25 and CIP is effectively reduced. These results suggest that CIP specifically inhibits both Cdk5 p25 complex activity and the tau hyperphosphorylation induced by Cdk5 p25. The elucidation of the molecular basis of p25 activation and CIP inhibition of Cdk5 activity may provide insight into mechanisms underlying the pathology of Alzheimer s disease and contribute to therapeutic strategies. Keywords Cdk5 p35 Cdk5 inhibitory peptide CIP Tau phosphorylation Alzheimer s disease. Cdk5 is a serine threonine kinase with close homology to the mitotic Cdks 1 2 . It plays a critical role in brain development and neuronal migration 3-5 . In contrast to other members of the Cdk family Cdk5 is activated by binding the neuron-specific noncyclin molecules p35 or p39 6-9 . Mice lacking p35 are viable and fertile but show .