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Apoptosis and survival Role of CDK5 in neuronal death and survival


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Apoptosis and survival Role of CDK5 in neuronal death and survival

Role of CDK5 in neuronal death and survival

Cyclin-dependent kinase 5 ( CDK5 ) is a member of the small serine/threoninecyclin-dependent kinase (CDK) family.

The best known role of CDK5 is its regulatoin of the cytoskeleton architectureof the central nervous system (CNS). There is also some evidence that links CDK5activity to regulation of the cytoskeleton, axon guidance, membrane transport, synapticfunction, dopamine signaling and drug addiction through it neuronspecific activator,cyclin-dependent kinase 5 regulatory subunit 1 ( CDK5R1(p35) ) [1].

CDK5R1(p35)/ CDK5 may stimulate cell survival (inhibit cell apoptosis) viaEpidermal growth factor receptor family of receptor tyrosine kinases ( ErbB ). Inthis case, Neuregulin-1- stimulated ErbB2 and ErbB3 are activated byCDK5R1(p35)/ CDK5 phosphorylation in their proline-directed Ser/Thr residues inthe C-terminal tail domain. This, in turn, activates Phosphoinositide-3-kinase (PI3K ), which induces 3-phosphoinositide dependent protein kinase-1 ( PDK1)-dependent activation of v-akt murine thymoma viral oncogene ( AKT ) [2]. Active AKT phosphorylates and down-regulates the molecules involved incell death (e.g. Caspase-9 and/or BCL2-antagonist of cell death ( BAD ))[3], [4].

In addition, CDK5R1(p35)/ CDK5 may depress cell apoptosis via directphosphorylation of c-Jun N-terminal kinase 3 ( JNK 3 ) on Thr131. It inhibits itskinase activity and leads to reduction of c-Jun phosphorylation [5].It is unknown, that exactly pathway leads from c-Jun to apoptosis in this case. Itis possible, that c-Jun acts via Cell division cycle 2, G1 to S and G2 to M (CDK1 ) [6], which in turn may activate BAD [7]and/or inhibit B-cell CLL/lymphoma 2 ( Bcl-2 ) [8].

Moreover, CDK5R1(p35)/ CDK5 may repress Nerve growth factor ( NGF )signaling. It is unknown whether NGF activates cell apoptosis via Src homology 2domain containing transforming protein 1 ( Shc )/ Son of sevenless homologies (Sos )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )/v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activatedprotein kinase kinase 1 ( MEK1 )/ Mitogen activated protein kinases ( Erk) pathway. In normally functioning neurons, CDK5R1(p35)/ CDK5 inhibitsMEK1 activity, thus repressing NGF/ Erk -dependent apoptosis [9].

On the other hand, it was shown, that CDK5R1(p35)/ CDK5 may activate cellapoptosis.

For example, CDK5 is activated and plays an important role in neuronal deathinduced by DNA damage [10]. The pathway leading to CDK5 activation atDNA damage is not known. It is possible, that signal from damaged DNA is transited viaProtein kinase C, delta ( PKC-delta )/ Shc/ Sos/ H-Ras/c-Raf-1/ MEK1/ Erk pathway [11], [10].DNA damage-stimulated Erk may phosphorylate Early growth response 1 ( EGR1), which in turn activates transcription of CDK5R1(p35). Then CDK5R1(p35)/CDK5 phosphorylates p53 tumor suppressor, which activates transcription ofBCL2-associated X protein ( BAX ) [10]. BAX stimulates cellapoptosis via caspases cascade [12].