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Cdk5, a Journey from Brain to Pain: Lessons from Gene Targeting

  • Tej K. Pareek
  • Ashok B. Kulkarni
Chapter

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a ubiquitously expressed proline-directed serine/threonine kinase. The monomeric form of Cdk5 is inactive and requires binding with its activator p35 and/or p39 to execute its kinase activity. Cdk5 was initially identified by purification from bovine brain extract and termed “Cdk5” because of its nucleotide sequence homology with human CDC2. Since the discovery of this kinase in 1992, it has been extensively studied by different laboratories to gain insights into its multiple roles in many important physiological systems. It is interesting to note that this kinase, which was initially considered as a postmitotic, neuron-specific kinase, has also been recognized as a key molecule in many cellular functions in non-neuronal tissues. We have now determined that this kinase was not only misnamed, as it neither requires binding to cyclin for activation, nor is it critically essential in the cell cycle, but was also not specific to neurons, as previously thought. Gene targeting is a very powerful tool for understanding the function of genes in human development and disease; in 2007, the Nobel Prize in Physiology or Medicine was awarded for introducing principles of specific gene modifications in mice by the use of embryonic stem cells. After the generation of the first gene-targeted mouse, our knowledge of specific gene functions has been immensely augmented by making use of gene-targeting techniques. In the last decade, we and others have employed functional genomics tools for a better understanding of Cdk5 biology. In this chapter, we will discuss the lessons learned from different strategies undertaken to understand Cdk5 biology.

Cyclin-dependent kinase 5 (Cdk5) is an ubiquitously expressed proline-directed serine/threonine kinase. The monomeric form of Cdk5 is inactive and requires binding with its activator p35 and/or p39 to execute its kinase activity. Cdk5 was initially identified by purification from bovine brain extract and termed “Cdk5” because of its nucleotide sequence homology with human CDC2 [1,2]. Since the discovery of this kinase in 1992, it has been extensively studied by different laboratories to gain insights into its multiple roles and its involvement in molecular mechanisms in many important physiological systems. It is interesting to note this kinase, which was initially considered as a postmitotic, neuron-specific kinase [3], has also been recognized as a key molecule in many cellular functions in non-neuronal tissues [4]. We have now determined that this kinase was not only misnamed, as it neither requires binding to cyclin for activation, nor is it critically essential in the cell cycle, but also cast aside the myth of its neuronal specificity.

Due to the colossal power of gene targeting in understanding the gene function and its importance in studying human health and disease, this year’s (2007) Nobel prize in Physiology or Medicine has been jointly awarded to Drs. Mario R. Capecchi, Martin J. Evans, and Oliver Smithies for introducing principles of specific gene modifications in mice by the use of embryonic stem cells. After the generation of first gene-targeted mouse [5,6] in their labs, our knowledge of understanding a specific gene function has immensely augmented by making use of gene-targeting techniques. In the last decade, we and others have employed functional genomics tools for a better understanding of Cdk5 biology. In this chapter we will discuss the lessons learned from different strategies undertaken to understand Cdk5 biology.

Keywords

Purkinje Cell Cdk5 Activity Migration Defect Cdk5 Kinase Activity Internal Granule Cell Layer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We would like to thank Drs. Roscoe Brady, Harish Pant, Elias Utreras, Akira Futatsugi, Veeranna, and Vinod Yaragudri for a critical reading of this chapter and significant contribution to our Cdk5 studies described in this chapter, and Harry Grant for editorial assistance. This work was supported by funds from the Divisions of Intramural Research of the National Institute of Dental and Craniofacial Research and the National Institute of Neurological Disorders and Stroke.

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Functional Genomics Section, Laboratory of Cell and Developmental BiologyNational Institute of Dental and Craniofacial Research, National Institutes of HealthBethesdaUSA

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