Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CDK inhibitor p21 (WAF-1/CIP-1/SDI-1) has been implicated in DNA damage-induced p53-mediated G1 arrest, as well as in physiological processes, such as cell differentiation and senescence, that do not involve p53 function. To determine the impact of p21 on normal development and cell-cycle regulation in vivo, we have generated transgenic mice that abundantly express p21 specifically in hepatocytes. During postnatal liver development, when transgenic p-21 protein becomes detectable, hepatocyte proliferation is inhibited dramatically. This disturbance causes a reduction in the overall number of adult hepatocytes, resulting in aberrant tissue organization, runted liver and body growth, and increased mortality. The transgenic p21 protein is associated with most, if not all, of the cyclin D1-CDK4 in liver but not significantly with other cyclin/CDK proteins, indicating the importance of cyclin D1-CDK4 function in normal liver development. The appearance of large polyploid nuclei in some hepatocytes indicates that p21 may also cause arrest during the G2 phase of the cell cycle. Significantly, partial hepatectomy failed to stimulate hepatocytes to proliferate in p21 transgenic animals. These results provide the first in vivo evidence that appropriate p21 levels are critical in normal development and further implicate p21 in the control of multiple cell-cycle phases.
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PMID:Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration. 859 76

G1 cyclin E controls the initiation of DNA synthesis by activating CDK2, and abnormally high levels of cyclin E expression have frequently been observed in human cancers. We have isolated a novel human cyclin, cyclin E2, that contains significant homology to cyclin E. Cyclin E2 specifically interacts with CDK inhibitors of the CIP/KIP family and activates both CDK2 and CDK3. The expression of cyclin E2 mRNA oscillates periodically throughout the cell cycle, peaking at the G1/S transition, and exhibits a pattern of tissue specificity distinct from that of cyclin E1. Cyclin E2 encodes a short lived protein whose turnover is most likely governed by the proteasome pathway and is regulated by phosphorylation on a conserved Thr-392 residue. Expression of the viral E6 oncoprotein in normal human fibroblasts increases the steady state level of cyclin E2, but not cyclin E1, while expression of the E7 oncoprotein upregulates both. These data suggest that the expression of these two G1 E-type cyclins may be similarly regulated by the pRb function, but distinctly by the p53 activity.
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PMID:Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3, is induced by viral oncoproteins. 984 Sep 43

To investigate the mode of action of the p16(INK4a) tumor suppressor protein, we have established U2-OS cells in which the expression of p16(INK4a) can be regulated by addition or removal of isopropyl-beta-D-thiogalactopyranoside. As expected, induction of p16(INK4a) results in a G1 cell cycle arrest by inhibiting phosphorylation of the retinoblastoma protein (pRb) by the cyclin-dependent kinases CDK4 and CDK6. However, induction of p16(INK4a) also causes marked inhibition of CDK2 activity. In the case of cyclin E-CDK2, this is brought about by reassortment of cyclin, CDK, and CDK-inhibitor complexes, particularly those involving p27(KIP1). Size fractionation of the cellular lysates reveals that a substantial proportion of CDK4 participates in active kinase complexes of around 200 kDa. Upon induction of p16(INK4a), this complex is partly dissociated, and the majority of CDK4 is found in lower-molecular-weight fractions consistent with the formation of a binary complex with p16(INK4a). Sequestration of CDK4 by p16(INK4a) allows cyclin D1 to associate increasingly with CDK2, without affecting its interactions with the CIP/KIP inhibitors. Thus, upon the induction of p16(INK4a), p27(KIP1) appears to switch its allegiance from CDK4 to CDK2, and the accompanying reassortment of components leads to the inhibition of cyclin E-CDK2 by p27(KIP1) and p21(CIP1). Significantly, p16(INK4a) itself does not appear to form higher-order complexes, and the overwhelming majority remains either free or forms binary associations with CDK4 and CDK6.
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PMID:Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. 1002 85

The tumor suppressor, retinoblastoma (Rb), is involved in both terminal mitosis and neuronal differentiation. We hypothesized that activation of the Rb pathway would induce cell cycle arrest in primary neural precursor cells, independent of the proposed function of cyclin-dependent kinases 4/6 (CDK4/6) to sequester the CIP/KIP CDK inhibitors (CKIs) p21 and p27 from CDK2. We expressed dominant negative adenovirus mutants of CDKs 2, 4, and 6 (dnCDK2, dnCDK4, and dnCDK6) in neural progenitor cells derived from E12.5 wild type and Rb-deficient mouse embryos. In contrast to previous studies, our results demonstrate that in addition to dnCDK2, the dnCDK4/6 mutants can induce growth arrest. Moreover, the dnCDK4/6-mediated inhibition is Rb-dependent. The dnCDK2 partially inhibited cell growth in Rb-deficient cells, suggesting that CDK2 may have additional targets. A previously proposed function of CDK4/6 is CKI sequestration, thereby preventing the resulting inhibition of CDK2, believed to be the key regulator of cell cycle. However, our immunoprecipitations revealed that the dominant negative CDK mutants could arrest cell growth despite their interaction with p21 and p27. Taken together, our results demonstrate that both CDK2 and CDK4/6 are crucial for cell cycle regulation. Furthermore, our data underscore the importance of the Rb regulatory pathway in neuronal development and cell cycle regulation, independent of CKI sequestration.
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PMID:The Rb-CDK4/6 signaling pathway is critical in neural precursor cell cycle regulation. 1091 95

p21 (WAF1/Cip1) is the only member of the CIP/KIP family which has a well-characterized PCNA-binding domain. p21 is known to have an important function in the coordination of the cellular pathways which are activated in response to DNA damage, though the significance of the p21-PCNA interaction is not completely clear. We have analyzed the effects of expressing a miniprotein containing the PCNA-binding domain of p21 upon the cell cycle and upon the proliferation of various cell types. We have compared this with the effect of expressing a mutant form which is defective in PCNA-binding, but which retains the secondary cyclin-CDK-inhibitory site. No PCNA-dependent effects were seen in the short term upon cell cycle distribution. However, clonogenic assays show that the GFP-peptide miniprotein can significantly suppress proliferation in a PCNA-dependent manner. In some cell types, however, the suppression of proliferation was not PCNA-dependent, suggesting that cellular environment is a contributory factor to the effect of this miniprotein. The capacity of this peptide sequence to suppress cell proliferation in vivo is of interest as the basis for the design of potential antiproliferative therapeutic agents.
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PMID:Inhibition of cell proliferation by the PCNA-binding region of p21 expressed as a GFP miniprotein. 1130 88

Saikosaponin a, a purified ingredient of Chinese herb with known antitumor activity, can inhibit cell growth and DNA synthesis of hepatoma cell line HepG2. Both mRNA and protein of the CDK inhibitor p-16(INK4a) and p-15(INK4b) in HepG2 were greatly induced by saikosaponin a while that of p-21(CIP), p-27(KIP) and other cell cycle related genes were not. In addition, reduced phosphorylation of RB protein is observed in saikosaponin a-treated HepG2. Staurosporin, one of the PKC inhibitors, significantly prevented the saikosaponin a induced growth inhibition suggesting PKC pathway be involved. On the other hand, the phorbol ester tumor promoter TPA (12-O-Tetredecanolyphorbol 13-acetate) also inhibited HepG2 growth and specifically induced p-16(INK4a) and p-15(INK4b) mRNA expression. The results suggest that both saikosaponin a and TPA-induced HepG2 growth inhibition are associated with p-15(INK4a) and p-16(INK4b) gene expression and might be mediated by PKC signaling pathway.
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PMID:Involvement of p-15(INK4b) and p-16(INK4a) gene expression in saikosaponin a and TPA-induced growth inhibition of HepG2 cells. 1144 23

dacapo encodes a CIP/KIP-type inhibitor of Cyclin E/Cdk2 complexes in Drosophila melanogaster. In the embryonic epidermis, dacapo expression starts during G2 of the final division cycle and is required for the arrest of cell cycle progression in G1 after the final mitosis. The onset of dacapo transcription is the earliest event known to be required for the epidermal cell proliferation arrest. To advance our understanding of the regulatory mechanisms that terminate cell proliferation at the appropriate stage, we have analyzed the control of dacapo transcription. We show that dacapo transcription is not coupled to cell cycle progression. It is not affected in mutants where proliferation is arrested either too early or too late. Moreover, upregulation of dacapo expression is not an obligatory event of the cell cycle exit process. During early development of the central nervous system, we cannot detect p27Dacapo during the final division cycle of ganglion mother cells, while it is expressed at later stages. The control of dacapo expression therefore varies in different stages and tissues. The dacapo regulatory region includes many independent cis-regulatory elements. The elements that control epidermal expression integrate developmental cues that time the arrest of cell proliferation.
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PMID:Drosophila p27Dacapo expression during embryogenesis is controlled by a complex regulatory region independent of cell cycle progression. 1180 25

Cyclin-dependent kinase-5 (Cdk5) is a serine/threonine kinase activated by its neuron-specific activator, p35, or its truncated form, p25. It has been proposed that the deregulation of Cdk5 activity by association with p25 in human brain tissue disrupts the neuronal cytoskeleton and may be involved in neurodegenerative diseases such as Alzheimer's disease. In this study, we demonstrate that a short peptide (amino acid residues 154-279; Cdk5 inhibitory peptide; CIP), derived from p35, specifically inhibits Cdk5 activity in vitro and in HEK293 cells cotransfected with the peptide and Cdk5/p25, but had no effect on endogenous cdc2 kinase activity. Moreover, we demonstrate that the phosphorylation of tau in HEK293 cells, cotransfected with Cdk5/p25 and CIP, is effectively reduced. These results suggest that CIP specifically inhibits both Cdk5/p25 complex activity and the tau hyperphosphorylation induced by Cdk5/p25. The elucidation of the molecular basis of p25 activation and CIP inhibition of Cdk5 activity may provide insight into mechanisms underlying the pathology of Alzheimer's disease and contribute to therapeutic strategies.
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PMID:A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells. 1223 May 54

Normal human B lymphocytes are sensitive to the growth-inhibitory action of transforming growth factor beta1 (TGFbeta1) whereas malignant B lymphoma cells are mostly resistant to TGFbeta1 effects. We examined the phosphorylation status of retinoblastoma protein and the activity of G(1) cyclin-dependent kinases (cdk) in TGFbeta1-sensitive malignant follicular lymphoma cells during the TGFbeta1 treatment. The kinase activity of cdk2, cdk4, and cdk6 was significantly reduced and hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373) was observed. We examined the composition of cdk complexes and the level of cdk inhibitors to explain the inhibitory action of TGFbeta1 toward cdk activity. Both cdk4 and cdk6 were notably dissociated from cyclin D cofactors, while cyclin E-cdk2 complexes remained coupled in TGFbeta1-treated cells. TGFbeta1-induced growth arrest was associated with notably increased binding of p21(WAF1) to cdk4 and cdk6. No induction of cdk-inhibitor molecules of INK family was observed in TGFbeta1-treated DoHH2 cells. As shown, TGFbeta1-induced growth arrest of malignant B cells was associated with the activation of CIP/KIP family members of cdk inhibitors.
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PMID:Cyclin D-cdk6 complex is targeted by p21(WAF) in growth-arrested lymphoma cells. 1249 Jan 53

Since little is known about the function of polypeptide growth factors as regulators of multiple cell cycles, we compared the ability of FGF1, PDGF-AB and serum to induce a second round of DNA synthesis in Swiss 3T3 cells previously exposed to either FGF1, PDGF-AB or serum during the first cell cycle using [14C]- and [3H]thymidine in a double labeling system to distinguish between the first and second cell cycles. Surprisingly, we observed that cells exposed to either FGF1 or PDGF-AB in the first cell cycle were unable to synthesize DNA in response to FGF1 or PDGF-AB in the second cell cycle; yet these cells responded well to serum as a second cycle mitogen. Interestingly, while cells exposed to either FGF1 or PDGF-AB in the second cycle displayed normal receptor-mediated signaling and expressed cyclin D and E, they, like senescent fibroblasts and endothelial cells, failed to express cyclin A, and the continuous exposure of cells to either FGF1 or PDGF-AB resulted in a decrease in the kinase activity of the cyclin E/cdk2 complex. In addition, an increased association of this complex was observed with p21 CIP in an FGF1-dependent manner as well as with p27 KIP in a PDGF-AB-dependent manner. Lastly, the downregulation of p21 expression using an antisense strategy was able to partially rescue the replicative response of Swiss 3T3 cells to FGF1 in the second cycle. These data suggest that (i) FGF1 and PDGF-AB may limit their mitogenic effect to a single cell cycle, (ii) entry into the second round of replication is serum dependent and (iii) the self-limiting nature of FGF1 and PDGF-AB correlates with the accumulation of the cdk inhibitors, p21 and p27, respectively.
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PMID:Stimulation of quiescent cells by individual polypeptide growth factors is limited to one cell cycle. 1550 56


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