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Regulation and Function of Cdk5 in the Nucleus

  • Qian Yang
  • Zixu Mao
Chapter

Abstract

Early studies have shown that Cyclin-dependent kinase 5 (Cdk5) and its regulators function in the neuronal cytoplasm to regulate a range of cellular processes. This seems to distinct Cdk5 from other more traditional Cdks. However, recent discoveries have now extended the role of Cdk5 to the nucleus. This chapter summarizes these novel findings. These include the detection of Cdk5 and its regulators in the nucleus, identification of nuclear targets of Cdk5, and regulation of nuclear Cdk5 and its activators.

Keywords

Glucocorticoid Receptor Neuronal Death Nuclear Transcription Factor Postmitotic Neuron Cdk5 Kinase Activity 
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

Acknowledgements

The authors apologize for not being able to cite all the relevant studies due to space limitation. This work is supported by NIH AG023695, NS048254, and ES0153170, and by the Robert W. Woodruff Health Sciences Center Fund (Z.M).

References

  1. Ahuja, H.S., Zhu, Y., and Zakeri, Z. (1997). Association of cyclin-dependent kinase 5 and its activator p35 with apoptotic cell death. Dev Genet 21, 258–267.PubMedCrossRefGoogle Scholar
  2. Dhavan, R., and Tsai, L.H. (2001). A decade of CDK5. Nat Rev Mol Cell Biol 2, 749–759.PubMedCrossRefGoogle Scholar
  3. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., and Tsai, L.H. (2007). Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182.Google Scholar
  4. Fu, A.K., Fu, W.Y., Ng, A.K., Chien, W.W., Ng, Y.P., Wang, J.H., and Ip, N.Y. (2004). Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proc Natl Acad Sci USA 101, 6728–6733.PubMedCrossRefGoogle Scholar
  5. Fu, X., Choi, Y.K., Qu, D., Yu, Y., Cheung, N.S., and Qi, R.Z. (2006). Identification of nuclear import mechanisms for the neuronal Cdk5 activator. J Biol Chem 281, 39014–39021.PubMedCrossRefGoogle Scholar
  6. Gao, C.Y., Zakeri, Z., Zhu, Y., He, H., and Zelenka, P.S. (1997). Expression of Cdk5, p35, and Cdk5-associated kinase activity in the developing rat lens. Dev Genet 20, 267–275.PubMedCrossRefGoogle Scholar
  7. Gong, X., Tang, X., Wiedmann, M., Wang, X., Peng, J., Zheng, D., Blair, L.A., Marshall, J., and Mao, Z. (2003). Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38, 33–46.CrossRefGoogle Scholar
  8. Gregoire, S., Tremblay, A.M., Xiao, L., Yang, Q., Ma, K., Nie, J., Mao, Z., Wu, Z., Giguere, V., and Yang, X.J. (2006). Control of MEF2 transcriptional ac-tivity by coordinated phosphorylation and sumoylation. J Biol Chem 281, 4423–4433.PubMedCrossRefGoogle Scholar
  9. Guidato, S., McLoughlin, D.M., Grierson, A.J., and Miller, C.C. (1998). Cyclin D2 interacts with cdk-5 and modulates cellular cdk-5/p35 activity. J Neurochem 70, 335–340.Google Scholar
  10. Hamdane, M., Bretteville, A., Sambo, A.V., Schindowski, K., Begard, S., Delacourte, A., Bertrand, P., and Buee, L. (2005). p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death. J Cell Sci 118, 1291–1298.PubMedCrossRefGoogle Scholar
  11. Ino, H., and Chiba, T. (1996). Intracellular localization of cyclin-dependent kinase 5 (CDK5) in mouse neuron: CDK5 is located in both nucleus and cytoplasm. Brain Res 732, 179–185.PubMedCrossRefGoogle Scholar
  12. Kawauchi, T., Chihama, K., Nabeshima, Y., and Hoshino, M. (2006). Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol 8, 17–26.PubMedCrossRefGoogle Scholar
  13. Kesavapany, S., Amin, N., Zheng, Y.L., Nijhara, R., Jaffe, H., Sihag, R., Gutkind, J.S., Takahashi, S., Kulkarni, A., Grant, P., and Pant, H.C. (2004). p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (RasGRF2) mediates Rac-dependent Extracellular Signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons. J Neurosci 24, 4421–4431.PubMedCrossRefGoogle Scholar
  14. Kesavapany, S., Pareek, T.K., Zheng, Y.L., Amin, N., Gutkind, J.S., Ma, W., Kulkarni, A.B., Grant, P., and Pant, H.C. (2006). Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor-1. Neurosignals 15, 157–173.PubMedCrossRefGoogle Scholar
  15. Kino, T., Ichijo, T., Amin, N.D., Kesavapany, S., Wang, Y., Kim, N., Rao, S., Player, A., Zheng, Y.L., Garabedian, M.J., et al. (2007). Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: clinical implications for the nervous system response to glucocorticoids and stress. Mol Endocrinol 21, 1552–1568.PubMedCrossRefGoogle Scholar
  16. Lacy, E.R., Wang, Y., Post, J., Nourse, A., Webb, W., Mapelli, M., Musacchio, A., Siuzdak, G., and Kriwacki, R.W. (2005). Molecular basis for the specificity of p27 toward cyclin-dependent kinases that regulate cell division. J Mol Biol 349, 764–773.PubMedCrossRefGoogle Scholar
  17. Lee, J.H., and Kim, K.T. (2007). Regulation of cyclin-dependent kinase 5 and p53 by ERK1/2 pathway in the DNA damage-induced neuronal death. J Cell Physiol 210, 784–797.PubMedCrossRefGoogle Scholar
  18. Lee, K.Y., Helbing, C.C., Choi, K.S., Johnston, R.N., and Wang, J.H. (1997). Neuronal Cdc2-like kinase (Nclk) binds and phosphorylates the retinoblastoma protein. J Biol Chem 272, 5622–5626.PubMedCrossRefGoogle Scholar
  19. Lee, K.Y., Rosales, J.L., Lee, B.C., Chung, S.H., Fukui, Y., Lee, N.S., Lee, K.Y., and Jeong, Y.G. (2004). Cdk5/p35 expression in the mouse ovary. Mol Cells 17, 17–22.PubMedGoogle Scholar
  20. Lew, J., Winkfein, R.J., Paudel, H.K., and Wang, J.H. (1992). Brain proline-directed protein kinase is a neurofilament kinase which displays high sequence homology to p34cdc2. J Biol Chem 267, 25922–25926.PubMedGoogle Scholar
  21. Li, Z., David, G., Hung, K.W., DePinho, R.A., Fu, A.K., and Ip, N.Y. (2004). Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repres-sion of transcription. J Biol Chem 279, 54438–54444.PubMedCrossRefGoogle Scholar
  22. Lin, H., Chen, M.C., Chiu, C.Y., Song, Y.M., and Lin, S.Y. (2007). Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. J Biol Chem 282, 2776–2784.PubMedCrossRefGoogle Scholar
  23. Lolli, G., and Johnson, L.N. (2005). CAK-Cyclin-dependent activating kinase: a key kinase in cell cycle control and a target for drugs? Cell Cycle 4, 572–577.PubMedCrossRefGoogle Scholar
  24. Mao, Z., Bonni, A., Xia, F., Nadal-Vicens, M., and Greenberg, M.E. (1999). Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286, 785–790.PubMedCrossRefGoogle Scholar
  25. Matsunaga, Y. (2000). [Expression of cyclin E in postmitotic cells in the central nervous system]. Kokubyo Gakkai Zasshi 67, 169–181.PubMedCrossRefGoogle Scholar
  26. Meyerson, M., Enders, G.H., Wu, C.L., Su, L.K., Gorka, C., Nelson, C., Harlow, E., and Tsai, L.H. (1992). A family of human cdc2-related protein kinases. Embo J 11, 2909–2917.PubMedGoogle Scholar
  27. Musa, F.R., Tokuda, M., Kuwata, Y., Ogawa, T., Tomizawa, K., Konishi, R., Takenaka, I., and Hatase, O. (1998). Expression of cyclin-dependent kinase 5 and associated cyclins in Leydig and Sertoli cells of the testis. J Androl 19, 657–666.PubMedGoogle Scholar
  28. Neystat, M., Rzhetskaya, M., Oo, T.F., Kholodilov, N., Yarygina, O., Wilson, A., El-Khodor, B.F., and Burke, R.E. (2001). Expression of cyclin-dependent kinase 5 and its activator p35 in models of induced apoptotic death in neurons of the substantia nigra in vivo. J Neurochem 77, 1611–1625.PubMedCrossRefGoogle Scholar
  29. Nikolic, M., Chou, M.M., Lu, W., Mayer, B.J., and Tsai, L.H. (1998). The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395, 194–198.Google Scholar
  30. O'Hare, M.J., Kushwaha, N., Zhang, Y., Aleyasin, H., Callaghan, S.M., Slack, R.S., Albert, P.R., Vincent, I., and Park, D.S. (2005). Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and exci-totoxic neuronal death. J Neurosci 25, 8954–8966.PubMedCrossRefGoogle Scholar
  31. Patrick, G.N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L.H. (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622.PubMedCrossRefGoogle Scholar
  32. Qu, D., Li, Q., Lim, H.Y., Cheung, N.S., Li, R., Wang, J.H., and Qi, R.Z. (2002). The protein SET binds the neuronal Cdk5 activator p35nck5a and modulates Cdk5/p35nck5a activity. J Biol Chem 277, 7324–7332.PubMedCrossRefGoogle Scholar
  33. Rosales, J., Han, B., and Lee, K.Y. (2003). Cdk7 functions as a cdk5 activating kinase in brain. Cell Physiol Biochem 13, 285–296.PubMedCrossRefGoogle Scholar
  34. Saito, T., Onuki, R., Fujita, Y., Kusakawa, G., Ishiguro, K., Bibb, J.A., Kishimoto, T., and Hisanaga, S. (2003). Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation. J Neurosci 23, 1189–1197.PubMedGoogle Scholar
  35. Smith, P.D., Mount, M.P., Shree, R., Callaghan, S., Slack, R.S., Anisman, H., Vincent, I., Wang, X., Mao, Z., and Park, D.S. (2006). Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J Neurosci 26, 440–447.PubMedCrossRefGoogle Scholar
  36. Tang, X., Wang, X., Gong, X., Tong, M., Park, D., Xia, Z., and Mao, Z. (2005). Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2. J Neurosci 25, 4823–4834.PubMedCrossRefGoogle Scholar
  37. Tsai, L.H., Takahashi, T., Caviness, Jr., V.S., and Harlow, E. (1993). Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development 119, 1029–1040.PubMedGoogle Scholar
  38. Ubeda, M., Kemp, D.M., and Habener, J.F. (2004). Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer's disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology 145, 3023–3031.PubMedCrossRefGoogle Scholar
  39. Ubeda, M., Rukstalis, J.M., and Habener, J.F. (2006). Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. J Biol Chem 281, 28858–28864.PubMedCrossRefGoogle Scholar
  40. Xiong, Y., Zhang, H., and Beach, D. (1992). D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71, 505–514.PubMedCrossRefGoogle Scholar
  41. Yang, H.S., Alexander, K., Santiago, P., and Hinds, P.W. (2003). ERM proteins and Cdk5 in cellular senescence. Cell Cycle 2, 517–520.PubMedCrossRefGoogle Scholar
  42. Zhang, J., Krishnamurthy, P.K., and Johnson, G.V. (2002). Cdk5 phosphorylates p53 and regulates its activity. J Neurochem 81, 307–313.PubMedCrossRefGoogle Scholar
  43. Zhang, Q., Ahuja, H.S., Zakeri, Z.F., and Wolgemuth, D.J. (1997). Cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. Dev Biol 183, 222–233.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Departments of Pharmacology and Neurology, Center for Neurodegenerative DiseaseEmory University School of MedicineAtlantaUSA

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