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

The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30%-50% of human gliobastoma multiforme (GBM). These mutations are associated usually with deletions of the INK4a-ARF locus, which encodes two gene products (p16(INK4a) and p19(ARF)) involved in cell-cycle arrest and apoptosis. We have investigated the role of EGFR mutation in gliomagenesis, using avian retroviral vectors to transfer a mutant EGFR gene to glial precursors and astrocytes in transgenic mice expressing tv-a, a gene encoding the retrovirus receptor. TVA, under control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGFR in cells in the glial lineage can induce lesions with many similarities to human gliomas. These lesions occur more frequently with gene transfer to mice expressing tv-a from the progenitor-specific nestin promoter than to mice expressing tv-a from the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, suggesting that tumors arise more efficiently from immature cells in the glial lineage. Furthermore, EGFR-induced gliomagenesis appears to require additional mutations in genes encoding proteins involved in cell-cycle arrest pathways. We have produced these combinations by simultaneously infecting tv-a transgenic mice with vectors carrying cdk4 and EGFR or by infecting tv-a transgenic mice bearing a disrupted INK4a-ARF locus with the EGFR-carrying vector alone. Moreover, EGFR-induced gliomagenesis does not occur in conjunction with p53 deficiency, unless the mice are also infected with a vector carrying cdk4. The gliomagenic combinations of genetic lesions required in mice are similar to those found in human gliomas.
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PMID:A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. 985 74

This study provides the first report that the same cytokine (interleukin-1 (IL-1)) can induce opposite effects on cyclin-dependent kinases (Cdks) and Cdk inhibitors (Cdkis) in the G1 phase even in the same type of cancer cells (papillary thyroid carcinoma cells). Cell cycle analysis revealed an increase in NIM1 cells and a decrease in NPA cells in the S and G2+M phases after treatment with IL-1alpha. The addition of IL-1alpha to NIM1 cells reduced the expression of p16 and p21 protein and induced the expression of Cdk2 and Cdk4 protein, which leads to the phosphorylation of retinoblastoma protein. The addition of IL-1alpha to NPA cells induced the expression of p27 protein and reduced the expression of Cdk2 protein, which leads to induction of p107 protein expression. It is of interest that p21 protein expression was not observed in NPA cells. These results suggest that several Cdks and Cdkis play a regulatory role in the G1 cell cycle progression and arrest induced by IL-1alpha in thyroid carcinoma cell lines.
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PMID:Interleukin-1alpha regulates G1 cell cycle progression and arrest in thyroid carcinoma cell lines NIM1 and NPA. 985 78

Contact inhibition is a well-known phenomenon, but the details of its mechanism are poorly understood. Recently, cyclin-dependent kinase inhibitors have been studied intensively with respect to their regulatory role in the cell cycle, and of them, p27(Kip1) is particularly involved in contact inhibition. p27(Kip1) is believed to be regulated primarily through posttranscriptional mechanisms. We now report that cyclin-dependent kinase inhibitors, including p27, are regulated differently at the mRNA level during contact inhibition in murine BALB/c-3T3 fibroblasts. The mRNA expression of p15, p16, and p27 was up-regulated as the cell density increased, but, on the contrary, the mRNA level of p21(Cip1/WAF1/Sdi1) markedly decreased when the cells became confluent. The protein levels of these genes were regulated in the same way as their mRNA levels, and cyclin-dependent kinase-2 activity was markedly inhibited on density-mediated growth arrest of the cells. These results indicate that the regulation of mRNA expression of cyclin-dependent kinase inhibitors appears to contribute to their protein levels and to the arrest of cell growth through contact inhibition.
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PMID:Opposite regulation of the expression of cyclin-dependent kinase inhibitors during contact inhibition. 988 Jul 94

CDKN2A (p16INK4A/MTS1) and CDKN2B (p15INK4B/MTS2) have recently been shown to be potent inhibitors of the cyclin D/cyclin-dependent kinase-4 complex. Both genes are candidates for the putative tumour suppressor genes located at chromosome 9p21 and are frequently inactivated in many human cancers through homozygous deletion. More recently, another reported pathway of inactivation involves loss of transcription associated with de novo methylation of the 5' CpG island of p16/MTS1 and p15/MTS2 in human cancers. We examined a total of 34 tumours from 30 hepatocellular carcinoma (HCC) patients for deletion, mutation and DNA methylation of these two genes by polymerase chain reaction (PCR) amplification, sequence analysis and Southern blot. Homozygous deletions of P16/MTS1 exon 1 were only identified in 1 of 30 cases (3%). Homozygous deletions of p15 exon 1 or exon 2 were found in 7 of 30 cases (13%). Automated sequencing analysis of p16 exon 1 and 2 and p15 exon 1 and 2 failed to demonstrate mutations in either p16 or p15 in any of these specimens. No aberrant 5' CpG island hypermethylation of p16 or p15 was found in any of the primary tumours by Southern blot. These data suggest that the p16/MTS1 gene has a limited role in HCC. However, deletions of the p15/MTS2 gene are found in 13% HCC and might be involved in a subset of HCC.
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PMID:Infrequent mutations and no methylation of CDKN2A (P16/MTS1) and CDKN2B (p15/MTS2) in hepatocellular carcinoma in Taiwan. 989 70

Transforming growth factor-beta1 (TGFbeta1) is inhibitory to most epithelia, but its role in the control of proliferation of prostatic epithelium is unclear. In some cells, TGFbeta1 inhibition is achieved by up-regulation of cyclin-dependent kinase (cdk) inhibitors including p15, p21 and p27. Our aims were to determine whether the effects of TGFbeta1 on human prostatic epithelial cell cycle kinetics were mediated by alterations in the levels of the cdk inhibitors p15, p16, p21 and p27 and hypo-phosphorylated retinoblastoma protein (Rb). Human prostatic epithelial cells in primary culture were grown in the presence of TGFbeta1 (0-10 ng/ml) for up to 4 days and proliferation assessed using a [3H]thymidine uptake assay. Levels of p15, p16, p21 and p27 were measured at both mRNA and protein level by means of a reverse transcriptase PCR-based assay and Western analysis. Rb and cdk2 levels were measured. Exogenous TGFbeta1 (0-5 ng/ml) inhibited proliferation. This was associated with blocking of the cell cycle at G1, and up to 4-fold increases in p15, p21 and p27 mRNA levels, but no change was observed in p16 mRNA levels; these changes were not blocked by cycloheximide. Increased levels of p15, p21 and p27 protein were also accompanied by increased levels of hypo-phosphorylated Rb and decreased cdk2 kinase activity. TGFbeta1 has mainly inhibitory effects on benign human prostatic epithelium, which are caused by up-regulation of cdk inhibitors, hypo-phosphorylation of Rb and delaying of the cell cycle in G1.
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PMID:Transforming growth factor-beta1 up-regulates p15, p21 and p27 and blocks cell cycling in G1 in human prostate epithelium. 992 95

DNA tumour viruses have evolved a number of mechanisms by which they deregulate normal cellular growth control. We have recently described the properties of a cyclin encoded by human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) which is able to resist the actions of p16(Ink4a), p21(Cip1) and p27(Kip1) cdk inhibitors. Here we investigate the mechanism involved in the subversion of a G1 blockade imposed by overexpression of p27(Kip1). We demonstrate that binding of K cyclin to cdk6 expands the substrate repertoire of this cdk to include a number of substrates phosphorylated by cyclin-cdk2 complexes but not cyclin D1-cdk6. Included amongst these substrates is p27(Kip1) which is phosphorylated on Thr187. Expression of K cyclin in mammalian cells leads to p27(Kip1) downregulation, this being consistent with previous studies indicating that phosphorylation of p27(Kip1) on Thr187 triggers its downregulation. K cyclin expression is not able to prevent a G1 arrest imposed by p27(Kip1) in which Thr187 is mutated to non-phosphorylatable Ala. These results imply that K cyclin is able to bypass a p27(Kip1)-imposed G1 arrest by facilitating phosphorylation and downregulation of p27(Kip1) to enable activation of endogenous cyclin-cdk2 complexes. The extension of the substrate repertoire of cdk6 by K cyclin is likely to contribute to the deregulation of cellular growth by this herpesvirus-encoded cyclin.
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PMID:Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus. 992 25

Telomerase is a ribonucleoprotein enzyme that adds hexanucleotide repeats TTAGGG to the ends of chromosomes. Telomerase activation is known to play a crucial role in cell-immortalization and carcinogenesis. Telomerase is shown to have a correlation with cell cycle progression, which is controlled by the regulation of cyclins, cyclin dependent kinases (cdks) and cyclin dependent kinase inhibitors (cdkis). Abnormal expression of these regulatory molecules may cause alterations in cell cycle with uncontrolled cell growth, a universal feature of neoplasia. Skin cancer is the most prevalent form of cancer in humans and the solar UV radiation is its major cause. Here, we investigated modulation in telomerase activity and protein expression of cell cycle regulatory molecules during the development of UVB-induced tumors in SKH-1 hairless mice. The mice were exposed to 180 mjoules/cm2 UVB radiation, thrice weekly for 24 weeks. The animals were sacrificed at 4 week intervals and the studies were performed in epidermis. Telomerase activity was barely detectable in the epidermis of non-irradiated mouse. UVB exposure resulted in a progressive increase in telomerase activity starting from the 4th week of exposure. The increased telomerase activity either persisted or further increased with the increased exposure. In papillomas and carcinomas the enzyme activity was comparable and was 45-fold higher than in the epidermis of control mice. Western blot analysis showed an upregulation in the protein expression of cyclin D1 and cyclin E and their regulatory subunits cdk4 and cdk2 during the course of UVB exposure and in papillomas and carcinomas. The protein expression of cdk6 and ckis viz. p16/Ink4A, p21/Waf1 and p27/Kip1 did not show any significant change in UVB exposed skin, but significant upregulation was observed both in papillomas and carcinomas. The results suggest that telomerase activation may be involved in UVB-induced tumorigenesis in mouse skin and that increased telomerase activity may be associated with G1 phase of the cell cycle.
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PMID:Activation of telomerase and its association with G1-phase of the cell cycle during UVB-induced skin tumorigenesis in SKH-1 hairless mouse. 1002 11

The D-type cyclins and their major kinase partners CDK4 and CDK6 regulate G0-G1-S progression by contributing to the phosphorylation and inactivation of the retinoblastoma gene product, pRB. Assembly of active cyclin D-CDK complexes in response to mitogenic signals is negatively regulated by INK4 family members. Here we show that although all four INK4 proteins associate with CDK4 and CDK6 in vitro, only p16(INK4a) can form stable, binary complexes with both CDK4 and CDK6 in proliferating cells. The other INK4 family members form stable complexes with CDK6 but associate only transiently with CDK4. Conversely, CDK4 stably associates with both p21(CIP1) and p27(KIP1) in cyclin-containing complexes, suggesting that CDK4 is in equilibrium between INK4 and p21(CIP1)- or p27(KIP1)-bound states. In agreement with this hypothesis, overexpression of p21(CIP1) in 293 cells, where CDK4 is bound to p16(INK4a), stimulates the formation of ternary cyclin D-CDK4-p21(CIP1) complexes. These data suggest that members of the p21 family of proteins promote the association of D-type cyclins with CDKs by counteracting the effects of INK4 molecules.
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PMID:Cyclin D-CDK subunit arrangement is dependent on the availability of competing INK4 and p21 class inhibitors. 1002 65

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 irreversible G1 arrest in senescent human diploid fibroblasts is probably caused by inactivation of the G1 cyclin-cyclin-dependent kinase (Cdk) complexes responsible for phosphorylation of the retinoblastoma protein (pRb). We show that the Cdk inhibitor p21(Sdi1,Cip1,Waf1), which accumulates progressively in aging cells, binds to and inactivates all cyclin E-Cdk2 complexes in senescent cells, whereas in young cells only p21-free Cdk2 complexes are active. Furthermore, the senescent-cell-cycle arrest occurs prior to the accumulation of the Cdk4-Cdk6 inhibitor p16(Ink4a), suggesting that p21 may be sufficient for this event. Accordingly, cyclin D1-associated phosphorylation of pRb at Ser-780 is lacking even in newly senescent fibroblasts that have a low amount of p16. Instead, the cyclin D1-Cdk4 and cyclin D1-Cdk6 complexes in these cells are associated with an increased amount of p21, suggesting that p21 may be responsible for inactivation of both cyclin E- and cyclin D1-associated kinase activity at the early stage of senescence. Moreover, even in the late stage of senescence when p16 is high, cyclin D1-Cdk4 complexes are persistent, albeit reduced by </=50% compared to young cells. We also provide new evidence that p21 may play a role in inactivation of the DNA replication factor proliferating cell nuclear antigen during early senescence. Finally, because p16 accumulates in parallel with the increases in senescence-associated beta-Gal activity and cell volume that characterize the senescent phenotype, we suggest that p16 upregulation may be part of a differentiation program that is turned on in senescent cells. Since p21 decreases after senescence is achieved, this upregulation of p16 may be essential for maintenance of the senescent-cell-cycle arrest.
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PMID:Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. 1002 98


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