View the Current Issue

Article

  • The EMBO Journal (2002) 21, 324 - 333
  • doi:10.1093/emboj/21.3.324

Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3

Bing-Sheng Li1, Lei Zhang2, Satoru Takahashi3, Wu Ma4, Howard Jaffe1, Ashok B. Kulkarni3 and Harish C. Pant1

  1. Laboratory of Neurochemistry, NINDS, NIH, Bethesda, MD 20892-4130, USA
  2. Behavioral and Endocrinology Branch, NIMH, NIH, Bethesda, MD 20892, USA
  3. Functional Genomics Unit, Gene Targeting Facility, NIDCR, NIH, Bethesda, MD 20892-4370, USA
  4. Center for Bio/Molecular Science and Engineering, Naval Research Laboratory, Washington, DC 20375, USA

Correspondence to:

Harish C. Pant, E-mail: panth@ninds.nih.gov

Received 16 July 2001; Accepted 14 November 2001; Revised 19 October 2001

Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase activated by associating with its neuron-specific activators p35 and p39. Analysis of cdk5-/- and p35-/- mice has demonstrated that both cdk5 and p35 are essential for neuronal migration, axon pathfinding and the laminar configuration of the cerebral cortex, suggesting that the cdk5–p35 complex may play a role in neuron survival. However, the targets of cdk5 that regulate neuron survival are unknown. Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation. Expression of cdk5 and p35 in HEK293T cells inhibits c-Jun phosphorylation induced by UV irradiation. These effects can be restored by expression of a catalytically inactive mutant form of cdk5. Moreover, cdk5-deficient cultured cortical neurons exhibit increased sensitivity to apoptotic stimuli, as well as elevated JNK3 activity and c-Jun phosphorylation. Taken together, these findings show that cdk5 may exert its role as a key element by negatively regulating the c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway during neuronal apoptosis.

  • Keywords:

    • apoptosis,
    • cdk5,
    • c-Jun,
    • JNK,
    • phosphorylation