Disease relevance of Cdc2a

• Renal ischemia reperfusion injury is known to shorten telomeres and upregulate stress-induced genes, such as the cyclin-dependent kinase (CDK) inhibitor p21 [1].
• Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exit the cell cycle and differentiate, we considered whether excess Cdk activity might contribute to this biology [2].
• In contrast, the excitotoxic component of ischemia/hypoxia is predominately regulated by Cdk5 and its activator p35, components of a cyclin-dependent kinase complex associated with neuronal development [3].
• Decreased expression of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) is common in breast cancer and is associated with poor prognosis. p27 is also an important mediator of steroidal regulation of cell cycle progression [4].
• There was an increase in podocyte expression of Cdc2, cyclin B1 and B2 and phosphorylated histone 3 in PHN rats, and in HIV transgenic mice [5].

High impact information on Cdc2a

• Entry into mitosis requires the activation of cdk1/cyclin B, while mitotic exit is achieved when the same kinase activity decreases, as cyclin B is degraded [6].
• In a wide variety of animal species, oocyte maturation is arrested temporarily at prophase of meiosis I (ref. 1). Resumption of meiosis requires activation of cyclin-dependent kinase-1 (CDK1, p34cdc2), one component of maturation-promoting factor (MPF) [7].
• Trrap-deficient cells fail to sustain mitotic arrest despite chromosome missegregation and disrupted spindles, and display compromised cdk1 activity [8].
• Meiosis arrest in Ccna1-/- males was associated with increased germ cell apoptosis, desynapsis abnormalities and reduction of Cdc2 kinase activation at the end of meiotic prophase [9].
• Cyclin A2 activates cdc2 (Cdk1) on passage into mitosis and Cdk2 at the G1/S transition [10].

Chemical compound and disease context of Cdc2a

• CONCLUSION/INTERPRETATION: Our data show that enalapril attenuates the glomerular expression of cyclin-dependent kinase inhibitors in diabetes and suggest a molecular mechanism of how angiotensin-converting enzyme inhibitors prevent renal hypertrophy in diabetes [11].
• Hyperthermia, the calcium ionophore A23187, and amino acid analogs (L-azetidine-2-carboxylic acid and L-canavanine) induced the formation of the major stress proteins, but failed to increase synthesis of p32 and p34 [12].
• Here, we ask whether the cyclin-dependent kinase (CDK) inhibitor, CYC202 (R-roscovitine), could attenuate or reverse existing renal disease in Tg26 mice, a well characterized HIV-1 transgenic mouse model of CG [13].
• Here we report that antibody prepared against p32/p34 purified from human A375 melanoma cells immunoprecipitated an antigen of similar molecular mass from a panel of human, rat, and murine cells following challenge with sodium arsenite [14].
• We found that after acute renal failure induced by either cisplatin injection or renal ischemia, induction of the p21 cyclin-dependent kinase (cdk) inhibitor is protective [15].

Biological context of Cdc2a

• Moreover, the significant reduction in hepatocyte mitosis was associated with diminished mRNA levels and nuclear expression of Cdc25B phosphatase and delayed accumulation of cyclin B1 protein, which is required for Cdk1 activation and entry into mitosis [16].
• As a result, cyclin-dependent kinase activity, Rb phosphorylation, and E2F target gene expression were restored to nearly normal levels, rendering cells responsive to normal growth signals [17].
• Cyclin a-CDK phosphorylation regulates MDM2 protein interactions [18].
• This is the first description that p130 may have a role in inhibiting CDK activity during senescence [19].
• The current studies address whether regulation of the cell cycle during lens fiber differentiation in normal lenses or in lenses in which pRB has been inactivated is accompanied by changes in expression of cyclin and cyclin-dependent kinase genes [20].

Anatomical context of Cdc2a

• Foxo3a was also found to facilitate the nuclear localization of p27(kip1) in oocytes, a cyclin-dependent kinase (Cdk) inhibitor that may serve to inhibit oocyte growth [21].
• Density-arrested fibroblasts contain low levels of cyclins E and A, and high levels of the Cdk inhibitor p27kip1 [22].
• In this study we showed that inducing apoptosis in mouse mesangial cells with ultraviolet (UV) irradiation was associated with increased cyclin A-cyclin dependent kinase (CDK) 2 activity [23].
• Immunohistochemical detection of Cdk1 was most apparent in early pachytene spermatocytes, while staining intensity diminished in diplotene and meiotically dividing spermatocytes, the cells in which cyclin A1 expression was strongest [24].
• All five Cdk family genes examined were expressed in Sertoli cells of the adult testis, which are no longer mitotically active [25].

Associations of Cdc2a with chemical compounds

• Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension [26].
• LY-294002, an inhibitor of phosphoinositide 3-kinase-PKB signalling, suppressed activation of PKB and CDK1 as well as resumption of meiosis [27].
• Silibinin-induced E2F1 was accompanied by an inhibition of apoptosis and decreases in p53 and cyclin-dependent kinase inhibitors [28].
• DNA sequence analysis revealed two point mutations in highly conserved regions of the gene: an isoleucine to valine change in the PSTAIR region, and a proline to serine change at the C-terminal region of the protein p34 [29].
• In transient transfection assays, transcriptional transactivation of the mouse muscle creatine kinase promoter by MyoD was enhanced by the Cdk inhibitors [30].

Physical interactions of Cdc2a

• Krüppel-like factor 5 promotes mitosis by activating the cyclin B1/Cdc2 complex during oncogenic Ras-mediated transformation [31].
• D-type cyclin/cyclin-dependent kinase (CDK) complexes regulate transit through the restriction point of the cell cycle, and thus are required for the initiation of DNA synthesis [32].
• Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes [33].
• In addition, cyclin D1/cyclin-dependent kinase (CDK) complex formation increased in the transgenic mice and was correlated with elevated CDK4 and CDK6 kinase activities [34].
• 6. These findings provide new evidence for a complex network of interacting pathways involving CDK/MAPK that control apoptosis downstream of KA receptor activation in excitotoxic neuronal cell death [35].

Enzymatic interactions of Cdc2a

• Cyclin dependent kinase (cdk) 4 and cdk6 have historically been understood to be D-cyclin kinases that phosphorylate pRb in the nucleus to regulate G1 phase of the cell cycle [36].
• Here, we show that cyclin B1/Cdc2 phosphorylates Pak1 in cells undergoing mitosis [37].
• Mature oocytes contained the MPF complex consisting of an active 34 kDa Cdc2 phosphorylated on threonine161 and a 49 kDa cyclin B1 or a 51 kDa cyclin B2 [38].

Regulatory relationships of Cdc2a

• p19ARF prevents G1 cyclin-dependent kinase activation by interacting with MDM2 and activating p53 in mouse fibroblasts [39].
• In addition, cyclin E binds to and activates Cdc2 [40].
• Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation [41].
• Together these studies demonstrate that c-myc regulates the expression of these cdk and suggest a role for c-myc in the G1/S transition [42].
• Thus, the redundant pathways consisting of cyclin proteolysis and CKIs control CDK activity during mitotic exit and contribute to maintenance of genome stability in mammalian cells [43].

Other interactions of Cdc2a

• p18(INK4c) belongs to the family of cyclin-dependent kinase inhibitory proteins that target the cyclin-dependent kinases and inhibit their catalytic activity [44].
• Since cyclin-dependent kinase (CDK) phosphorylation of Py T Ag is required for its replication function, we hypothesize that pRb interferes with this phosphorylation event [45].
• PKB (protein kinase B, also called AKT) is implicated in CDK1 activation in lower species [27].
• In addition, the levels of the cyclin-dependent kinase inhibitors p27(KIP1), p21(WAF1) and the tumor suppressor p53 were increased in the livers obtained from infected mice [46].
• These results suggest that Ras, along with the activation of additional pathways, is required for the generation of G1 CDK activity, and that activation of cyclin E-dependent kinase in particular depends on the cooperative action of Ras and Myc [47].

Analytical, diagnostic and therapeutic context of Cdc2a

• The expression of another CDK inhibitor, namely p16, was differentially regulated, depending on the time of reperfusion [1].
• We examined the modulation of CDK activity by these proteins after 70% partial hepatectomy (PH), an in vivo model of synchronous hepatocyte cell cycle progression [48].
• METHODS: The expression of mitotic cell cycle proteins (phosphorylated Histone 3, Cdc2, cyclin B1 and B2) was examined by immunohistochemistry in kidneys of embryonal mice, transgenic HIV-mice, and rats with experimental membranous nephropathy (passive Heymann nephritis, PHN) [5].
• Western blot analysis showed that Cdc2 remained phosphorylated in cAMP microinjected embryos by the time when control embryos were at metaphase and showed dephosphorylated Cdc2; conversely, Cdc2 dephosphorylation was accelerated in PKI-microinjected embryos [49].
• Quantitative immunoblotting of the column fractions with antibodies raised against p34, the product of the fission yeast cdc2 gene, revealed complete coelution of the H1K activity and a 34 kd anti-cdc2 cross-reactive protein [50].

References