Disease relevance of Cdc2a

• The results suggest that the toxicity exerted by ET-743 in the rat liver is a consequence of biliary rather than hepatocellular damage and that it is accompanied by a wave of mitogenic activity, which may be driven by the transcriptional increase in Cdc2a expression [1].
• Thus, our results have established a direct transcriptional link between glucocorticoid receptor signaling and the regulated promoter activity of a CDK inhibitor gene that is involved in the cell cycle arrest of hepatoma cells [2].
• The goal of this study was to clarify the role of p21, a cyclin-dependent kinase inhibitor, in acute renal failure (ARF) [3].
• Regulation of cyclin-dependent kinase inhibitors by mitogen-activated protein kinase in angiotensin II-stimulated vascular smooth muscle cell hypertrophy [4].
• Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist [5].

High impact information on Cdc2a

• Vertebrate eggs are arrested at metaphase of meiosis II with stable cyclin B and high cyclin B/Cdc2 kinase activity [6].
• Although p21, an inhibitor of cyclin-dependent kinase (Cdk) that is induced by DNA damage may partly account for the arrest in G1 (ref. 1), the mechanism is little understood [7].
• Here we show that when a constitutively active mutant of calmodulin-dependent protein kinase II (CaM KII) is added to a CSF extract, cyclin degradation and Cdc2 kinase inactivation occur even in the absence of Ca2+, and the extract loses its ability to cause metaphase arrest when transferred into embryos [8].
• Finally, the direct microinjection of constitutively active CaM KII into unfertilized eggs inactivates Cdc2 kinase and CSF, even in the absence of a Ca2+ transient [8].
• Expression of dominant-negative mutants of cdk5 (cdk5N144 and cdk5T33) inhibited neurite outgrowth, which was rescued by coexpression of the wild-type proteins [9].

Chemical compound and disease context of Cdc2a

• Aortic cyclin-dependent kinase protein was significantly (P = .0001) elevated in the three homocysteine-treated groups, and mRNA cyclin-dependent kinase levels were significantly elevated in the rats given the 50 and 100 mg/kg body weight per day protocol [10].
• Importantly, flavopiridol had no effect on core body temperature, suggesting that the mechanism of neuroprotection was through cyclin-dependent kinase inhibition but not through hypothermia [11].
• The differential activation of cyclin and cyclin-dependent kinase genes by the adenovirus E1A gene product (E1A) or serum factors was studied with a rat 3Y1 derivative cell line, g12-21, in which the E1A12S cDNA can be expressed in response to dexamethasone (dex) [12].
• Overexpression of cdk Inhibitor p16INK4a by adenovirus vector inhibits cardiac hypertrophy in vitro and in vivo: a novel strategy for the gene therapy of cardiac hypertrophy [13].
• Also, there was a decreased association of cyclin D and cyclin dependent kinase in susceptible tumors, supporting the hypothesis of a physical and possibly functional loss of pRb in the diethylstilbestrol-induced pituitary tumor [14].

Biological context of Cdc2a

• Cdc2-mediated phosphorylation of the gap junction protein, connexin43, during mitosis [15].
• CONCLUSIONS: Daily administration of low dose TA makes cell cycle open and G1 progress, possibly due to cyclin D1, CDK4 and CDK 6, their transporter p21(CIP1), and inactive p16(INK4a), which occur at quiescent hepatocytes, not stem cells [16].
• BACKGROUND AND AIMS: Eukaryotic cell cycle is regulated by signal transduction pathways mediated by complexes of cyclin dependent kinases (CDKs) and their partner cyclins, or by interaction with CDK inhibitors [16].
• Because pRb phosphorylation is regulated by cyclin-dependent kinases (CDK), we investigated CDK2 and CDK4 activities and the expression of CDK inhibitor p21(waf1/cip1/sdi1) (p21) [17].
• The resistance to apoptosis upon serum-starved treatment was correlated with an increase in the rate of the G1 phase in the cell cycle due to up-regulation of the cyclin-dependent kinase inhibitor p21 [18].

Anatomical context of Cdc2a

• We consider a model in which the PC12 cell cycle is arrested as p21 accumulates and attains inhibitory levels relative to Cdk/cyclin complexes [19].
• p21WAF1 cyclin-dependent kinase inhibitor has been implicated in the control of proliferation, differentiation, and death in various cell lines [20].
• CONCLUSIONS/INTERPRETATION: The expression of cyclin-dependent kinase inhibitor p21, which can be induced by oxidative stress, increases in pancreatic islet cells upon development of diabetes [21].
• We report here a specific behavior of members of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors during development of the rat liver and proliferation of normal hepatocytes [22].
• One mechanism by which nitric oxide (NO) may inhibit this process is through the upregulation of the cyclin-dependent kinase inhibitor p21, which induces a G0/G1 cell cycle arrest, leading to an inhibition of vascular smooth muscle cell (VSMC) proliferation [23].

Associations of Cdc2a with chemical compounds

• In these cells, dexamethasone, a synthetic glucocorticoid, stimulated a rapid and selective increase in expression of the p21 cyclin-dependent kinase (CDK) inhibitor mRNA and protein and virtually abolished CDK2 phosphorylation of the retinoblastoma protein [2].
• LY-294002 blocked the Ha-Ras-induced expression of cyclin D1, cyclin-dependent kinase (CDK) 2, and increased the levels of p27(kip) [24].
• We also found that two other proteins, the cyclin dependent kinase inhibitor p21 and DNA mismatches repair MSH2, whose encoding genes are well known target of p53, were upregulated by glutamate [25].
• We postulated that the differential response of vascular smooth muscle cells (VSMCs) to Ang II is mediated by the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1), which is abundant in quiescent cells and drops after serum stimulation [26].
• In primary neuronal and astrocyte cultures, cell cycle inhibition (including the cyclin-dependent kinase inhibitors flavopiridol, roscovitine, and olomoucine) reduced up-regulation of cell cycle proteins, limited neuronal cell death after etoposide-induced DNA damage, and attenuated astrocyte proliferation [27].

Physical interactions of Cdc2a

• Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc [28].
• It is well established that cyclin B1 protein forms a complex with cyclin-dependent kinase 1 (CDK1), which, when activated, initiates mitosis [29].

Regulatory relationships of Cdc2a

• In this study we demonstrate the anti-mitogenic, pro-apoptotic role of the zinc finger transcription factor Sp1 in vascular SMCs and define the underlying molecular mechanism via its capacity to repress the expression of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 at the level of transcription, mRNA, and protein [30].
• Ad-DN-ERK and Ad-DN-JNK suppressed PDGF-BB-induced downregulation of cyclin-dependent kinase inhibitor p27Kip1, whereas Ad-DN-p38 decreased PDGF-BB-induced upregulation of p21Cip1 [31].
• These effects resulted in the inhibition of mitogenic stimulation of cyclin-dependent kinases activated by cyclins D1 and E. These data demonstrate that PPARgamma ligands are antiproliferative drugs that act by modulating cyclin-dependent kinase inhibitors; they may provide a new therapeutic approach for proliferative vascular diseases [32].

Other interactions of Cdc2a

• Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2 [33].
• In accord with this is the observation that activation of M+ Akt:ER* led to decreased expression of the cyclin-dependent kinase inhibitor p27Kip1 with a concomitant increase in cyclin-dependent kinase-2 activity [34].
• HES-1 expression strongly repressed transcription of the p21(cip1) promoter, a cyclin-cyclin-dependent kinase inhibitor up regulated during NGF-induced differentiation, and the H-3/4 domain is necessary for this repression [35].
• METHODS AND RESULTS: Lesion formation was evaluated in balloon-injured carotid arteries of naive and adenovirus-immunized rats that were infected with adenoviral constructs expressing Fas ligand (Ad-FasL), the cyclin-dependent kinase inhibitor p21 (Ad-p21), or beta-galactosidase (Ad-betagal) [36].
• The activity of the cyclin-dependent kinase inhibitor p27 is controlled by its concentration and subcellular localization [37].

Analytical, diagnostic and therapeutic context of Cdc2a

• To characterize this growth arrest, we examined the activity of cyclin-dependent kinase (Cdk) 2 in unexposed liver and in AAF-exposed liver after growth induction by partial hepatectomy (PH) [38].
• The cell cycle regulatory enzyme, cdk (cyclin-dependent kinase) 2 kinase, is activated in the rat carotid artery after balloon angioplasty injury, and may mediate smooth muscle proliferation [39].
• We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury [40].
• Western blot analysis showed that the amount of Cdc2 increased when either rat kidney fibroblasscr2 or scr3 was introduced into the cdc2-L7 and cdc13-117 mutant cells of S.pombe [41].
• Immunohistochemistry of formalin-fixed liver demonstrated a cytosolic localization of immunoreactive CDK1 and nuclear localization of immunoreactive PCNA in proliferating cells of WY14,643-treated rat livers [42].

References