Zheng Ya-Li, Li Bing-Sheng, Amin Niranjana D, Albers Wayne, Pant Harish C
Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda 20892, USA.
Eur J Biochem. 2002 Sep;269(18):4427-34. doi: 10.1046/j.1432-1033.2002.03133.x.
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.
细胞周期蛋白依赖性激酶5（Cdk5）是一种丝氨酸/苏氨酸激酶，由其神经元特异性激活剂p35或其截短形式p25激活。有人提出，在人类脑组织中，Cdk5与p25结合导致其活性失调，会破坏神经元细胞骨架，并可能与阿尔茨海默病等神经退行性疾病有关。在本研究中，我们证明了一种源自p35的短肽（氨基酸残基154 - 279；Cdk5抑制肽；CIP）在体外以及在与该肽和Cdk5/p25共转染的HEK293细胞中特异性抑制Cdk5活性，但对内源性cdc2激酶活性没有影响。此外，我们证明了在与Cdk5/p25和CIP共转染的HEK293细胞中，tau的磷酸化被有效降低。这些结果表明，CIP特异性抑制Cdk5/p25复合物活性以及由Cdk5/p25诱导的tau过度磷酸化。阐明p25激活和CIP抑制Cdk5活性的分子基础可能为深入了解阿尔茨海默病的病理机制提供线索，并有助于制定治疗策略。
