Disease relevance of Cdk5r1

• These results, therefore, provide a strategy to address, and possibly ameliorate, the pathology of neurodegenerative diseases that may be a consequence of aberrant p25 activation of Cdk5, without affecting 'normal' Cdk5 activity [1].
• In rats without IT, the p35 levels slightly decreased after ischemia or reperfusion, whereas the levels of p25 (the truncated form of p35) were much higher than those in sham control rats after ischemia and remained elevated during reperfusion [2].
• Here, the levels of two calpain-specific substrates, p35 protein and eukaryotic initiation factor 4G (eIF4G), as well as its physiological regulator calpastatin, were investigated in a rat model of transient global cerebral ischemia with or without ischemic tolerance (IT) [2].
• In conclusion, pre-treatment with ASA induces tolerance against hypoxia/reoxygenation damage in spinal cord cultures by restoring Cdk5 and p35 protein expression [3].
• Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons [4].

Psychiatry related information on Cdk5r1

• Recently, it was shown that conversion of cdk5 activator protein p35 to a C-terminal fragment p25 promotes a deregulation of cdk5 activity, which may contribute to neurodegeneration in Alzheimer's disease [5].

High impact information on Cdk5r1

• These results suggest that Cdk5/p35 may be a drug target for the regulation of glucose-stimulated insulin secretion [6].
• Immunohistochemistry was used to localize p35 to a raphe of primitive glial ependymal cells in the median one-third of the floor plate in the central nervous system (CNS) of rat embryos [7].
• We show that neuronal infections with Cdk5 inhibitory peptide (CIP) selectively inhibit p25/Cdk5 activity and suppress the aberrant tau phosphorylation in cortical neurons [1].
• Activated tyrosine kinases therefore regulate the association of Shc proteins with p23 and may thereby control the stimulation of an Shc-mediated signal transduction pathway [8].
• A dominant-negative mutant of cdk5 blocked both p35- and p39-induced neurite extension as well as basic fibroblast growth factor (bFGF)-induced neuronal differentiation [9].

Chemical compound and disease context of Cdk5r1

• Our results showed that broad-spectrum inhibitors of the caspases, namely the baculovirus p35 gene and the peptide benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, effectively inhibit the death of both naive and neuronal PC12 cells [10].

Biological context of Cdk5r1

• These latter results agree with some previous studies showing that phosphorylation regulates proteasomal degradation of p35 [11].
• Furthermore, transfection and expression in chromaffin cells of a neural specific Cdk5 activator, p25, led to a strong increase in nicotinic agonist-induced secretory responses [12].
• It has been suggested that the conversion of p35 to p25 by the protease calpain is involved in neuronal cell death [13].
• We have therefore examined its expression and that of its known activators, p35, p39 and p67, in models of induced apoptosis in neurons of the substantia nigra [14].
• In addition, we show that up-regulation of cdk5/p25 is unrelated to inhibition of the activity of myocyte enhancer factor 2, a pro-survival transcription factor [15].

Anatomical context of Cdk5r1

• Here we show that the p35 transcript and protein are also present in the testis, and an active Cdk5.p35 complex exists in this tissue as well [16].
• In vitro ODF phosphorylation by Cdk5.p35 and decreased in vivo sperm tail ODF phosphorylation in p35-deficient mice indicate that Cdk5.p35 is an integral component of ODF and that ODF is a functional Cdk5.p35 target in the testis [16].
• Cdk5 and p35 are prominently observed in elongating spermatid tails, particularly over the tail outer dense fibers (ODF) [16].
• When tau and active kinase (Cdk5 and p25) were cotransfected in to COS cells, there was robust tau phosphorylation [17].
• Cdk5 and p35 are highly localized in the growth cone of cultured neurons, and Cdk5 activity is associated with neurite outgrowth [18].

Associations of Cdk5r1 with chemical compounds

• Different factors, such as maturation state of neurons or desensitization properties of non-NMDA receptors, may determine which receptor predominantly mediates the effect of glutamate on p35 cleavage [19].
• The data suggest that both NMDA and non-NMDA receptors are able to induce p35 cleavage [19].
• Treatment of brain homogenate with okadaic acid in the presence of ATP led to accumulation of p35 phosphorylated also by a kinase that was not inhibited by roscovitine [11].
• The phosphatase inhibitor okadaic acid induced p35 degradation in neuronal cultures which was sensitive to the proteasome inhibitor lactacystin [11].
• Cyclothiazide (CTZ), an inhibitor of AMPA receptor desensitization, enhanced glutamate-induced p35 cleavage [19].

Physical interactions of Cdk5r1

• Activity and regulation of p35/Cdk5 kinase complex [20].

Enzymatic interactions of Cdk5r1

• The calpain protease has been shown to cleave p35 [11].

Regulatory relationships of Cdk5r1

• Cyclin-dependent kinase 5 (Cdk5) is a serine-threonine kinase that is activated by the binding of p35 or p39 regulatory protein [18].

Other interactions of Cdk5r1

• Both N-methyl-D-aspartate (NMDA) and non-NMDA receptors mediate glutamate-induced cleavage of the cyclin-dependent kinase 5 (cdk5) activator p35 in cultured rat hippocampal neurons [19].
• The phosphorylation site in p35 that might be involved in preventing calpain cleavage was distinct from the phosphorylation site involved in facilitating proteasomal degradation [13].
• Serum IL-2 and interferon-gamma levels in the IL-12 p35 siRNA-transfected DCs treatment group were both significantly lower than in control groups at 7 days after transplantation [21].

Analytical, diagnostic and therapeutic context of Cdk5r1

• Although IT did not promote significant changes in p35 and p25 levels, it induced a slight increase in calpastatin and eIF4G levels in the hippocampal subregions after 4 h of reperfusion [2].
• The p35 recovered in the pellet after centrifugation could then be cleaved to p25 by purified calpain [22].
• To determine whether the two activators are expressed in different cells throughout the nervous system and during development, we compared the tissue distributions of cdk5, p35, and p39 mRNAs in the rat using in situ hybridization [23].
• In addition to the induction of mRNA expression, the total Cdk5 and p35-associated kinase activity in muscle increased prominently after nerve denervation [24].
• Prolongation of rat intestinal allograft survival by administration of donor interleukin-12 p35-silenced bone marrow-derived dendritic cells [21].

References