Disease relevance of Cdk5r1

• Targeted expression of anti-apoptotic protein p35 in oligodendrocytes reduces delayed demyelination and functional impairment after spinal cord injury [1].
• These results suggest that defective axonal fasciculation and guidance may be primary responses to the loss of p35 in the cortex [2].
• Caspase inhibition by Z-VAD-fmk or transfection with the baculovirus inhibitor p35 did not inhibit doxorubicin (DX)-induced cell death, yet suppressed the immunogenicity of dying tumor cells in several rodent models of neoplasia [3].
• Antisera to the major structural protein of other retroviruses did not precipitate equine infectious anemia virus p25 [4].
• Immunoelectron microscopy showed that p25 was present in the nuclei of OpMNPV-infected cells and localized to the envelopes surrounding polyhedron-derived virions [5].

Psychiatry related information on Cdk5r1

• These results suggest that, in women, the production of p25 in Alzheimer's disease could be a compensation for some early learning and memory deficits [6].
• In the Morris water maze the p25 mutants were normal in learning an initial platform location, but surprisingly reversal learning was improved when the platform position was changed [7].
• As p25 expression can improve learning and memory, p25 formation could be a compensatory mechanism for learning and memory deficits in Alzheimer's disease [7].
• Mice deficient in Cdk5, p35, or both p35 and p39 display the hallmarks of disturbed cortical development, including cortical layer inversion, neuronal disorientation, and abnormal fiber infiltration [8].
• The p25 transgenic mice display increased spontaneous locomotor activity and differences from control in the elevated plus-maze test [9].

High impact information on Cdk5r1

• Hence, our findings suggest that inside-out layering requires distinct functions of Reelin and p35/Cdk5 signaling, with the latter being important for proper glia-guided migration [10].
• In the p35(-/-) neocortex, the classic modes of radial migration--somal translocation and locomotion--were largely replaced by a distinct mode of migration: branched migration [10].
• Current mouse models expressing p25, however, fail to rigorously recapitulate these phenotypes in vivo [11].
• Here, we generated inducible transgenic mouse lines overexpressing p25 in the postnatal forebrain [11].
• Finally, phosphorylation of both proteins was undetectable in p35-deficient mice [12].

Chemical compound and disease context of Cdk5r1

• The effects of insulin, cycloheximide and phalloidin on the content of actin and p35 in extracts prepared from the nuclear fraction of Krebs II ascites cells [13].

Biological context of Cdk5r1

• Mouse Cdk5r was mapped to a position on mouse chromosome 11 [14].
• The most notable features of Cdk5r are the absence of introns in the amino acid coding region and the high homology of amino acid sequence among species [14].
• The mouse gene encoding p35, Cdk5r, was isolated from a mouse 129/SvJ genomic library, and the genomic structure of Cdk5r was characterized [14].
• The cdk5 inhibitor roscovitine increased anterograde axonal transport of GFP-M and CFP-tau; transfection with cdk5/p25 inhibited transport of both [15].
• CONCLUSION: Staurosporine-induced increase in Cdk5 protein levels and the cleavage of p35 to p25 may contribute to neuronal apoptosis [16].

Anatomical context of Cdk5r1

• We find that low levels of p25 during development induce a partial rescue of the p35-/- phenotype in several brain regions analyzed, including a rescue of cell positioning of a subset of neurons in the neocortex [17].
• These results indicate that Cdk5/p35 and Reelin signaling regulates the selective mode of neuronal migration in the developing mouse hindbrain [18].
• Mice lacking Cdk5/p35 display migration defects of the cortical neurons in the cerebrum and cerebellum [18].
• The unusual presence of nonphosphorylated neurofilament (NF) in aberrant axon fascicles and the relocation of tau and MAP2B from cell bodies and proximal neuronal processes to more distal sites of the neuropil in p35-/- mouse brain implicate p35 in neuronal trafficking, particularly in dynein-driven retrograde transport [19].
• In the double-null mice of p35 and either Dab1 or Reelin, additional migration defects occur in the Purkinje cells in the cerebellum and in the pyramidal neurons in the hippocampus [20].

Associations of Cdk5r1 with chemical compounds

• We report here that increased Cdk5 activity, as a result of p35 but not of Cdk5 overexpression, leads to attenuation of cocaine-mediated dopamine signaling [21].
• We report here that glutamate, acting via NMDA or kainate receptors, can induce a transient Ca(2+)/calmodulin-dependent activation of Cdk5 that results in enhanced autophosphorylation and proteasome-dependent degradation of a Cdk5 activator p35, and thus ultimately down-regulation of Cdk5 activity [22].
• Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase activated by associating with its neuron-specific activators p35 and p39 [23].
• Cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase that displays kinase activity predominantly in neurons, is activated by two non-cyclin activators, p35 or p39 [24].
• To gain insight into the mechanisms that underlie these defects, we examined the organization of landmark structures formed during cortical development and the migratory behavior of p35(-/-) cortical neurons by using bromodeoxyuridine labeling [25].

Physical interactions of Cdk5r1

• We report here that the Cdk5/p35 complex associates with STAT3 and phosphorylates STAT3 on the Ser-727 residue in vitro and in vivo [26].
• Novel interaction between nuclear co-activator CBP and the CDK5 activator binding protein - C53 [27].

Enzymatic interactions of Cdk5r1

• The ability of Cdk5 to phosphorylate substrates is dependent on activation by its neuronal-specific activators p35 and p39 [28].

Regulatory relationships of Cdk5r1

• Our results indicate that tumor necrosis factor-alpha (TNF-alpha) activates p35 promoter activity in a dose- and time-dependent manner and concomitantly up-regulates Cdk5 activity [29].

Other interactions of Cdk5r1

• Our data suggest that focal deregulation of cdk5/p25 in axons leads to cytoskeletal abnormalities and eventual neurodegeneration in NPC [30].
• Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain [18].
• The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons [31].
• Caspase inhibition protected p23 from degradation in several cell lines [32].
• Here, IL-12-deficient p35(- / -) and p40(- / -) mice were used to examine the role of endogenous IL-12 and p40 homodimer during in vivo development of exogenous antigen-driven responses [33].

Analytical, diagnostic and therapeutic context of Cdk5r1

• The mouse Cdk5r transcript was detected only in the brain by Northern blot analysis [14].
• Molecular cloning and chromosomal mapping of the mouse gene encoding cyclin-dependent kinase 5 regulatory subunit p35 [14].
• We show by Western blotting and immunohistochemistry that the known Cdk5 activator, p35, is also present in the mouse ovary [34].
• Whereas radioimmunoassay titers for the major protein, p25, were 500- to 1,000-fold higher than titers in immunodiffusion, for clinical purposes these two procedures were equivalent [4].
• Phorbol dibutyrate induces a dramatic increase in the p34cdc2 protein level as well as the appearance of p35-p36 forms of cdc2 on Western blot [35].

References