Regulation and Function of Cdk5 in the Nucleus
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.
KeywordsGlucocorticoid Receptor Neuronal Death Nuclear Transcription Factor Postmitotic Neuron Cdk5 Kinase Activity
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).
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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