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)

A novel 761-amino-acid transcription factor, DMP1, contains a central DNA binding domain that includes three imperfect myb repeats flanked by acidic transactivating domains at the amino and carboxyl termini. D-type cyclins associate with a region of the DMP1 DNA binding domain immediately adjacent to the myb repeats to form heteromeric complexes which detectably interact neither with cyclin-dependent kinase 4 (CDK4) nor with DNA. The segment of D-type cyclins required for its interaction with DMP1 falls outside the "cyclin box," which contains the residues predicted to contact CDK4. Hence, D-type cyclin point mutants that do not interact with CDK4 can still bind to DMP1. Enforced coexpression of either of three D-type cyclins (D1, D2, or D3) with DMP1 in mammalian cells canceled its ability to activate gene expression. This property was not shared by cyclins A, B, C, or H; did not depend upon CDK4 or CDK2 coexpression; was not subverted by a mutation in cyclin D1 that prevents its interaction with CDK4; and was unaffected by inhibitors of CDK4 catalytic activity. Introduction of DMP1 into mouse NIH 3T3 fibroblasts inhibited entry into S phase. Cell cycle arrest depended upon the ability of DMP1 to bind to DNA and to transactivate gene expression and was specifically antagonized by coexpression of D-type cyclins, including a D1 point mutant that does not bind to CDK4. Taken together, these findings suggest that DMP1 induces genes that inhibit S phase entry and that D-type cyclins can override DMP1-mediated growth arrest in a CDK-independent manner.
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PMID:Gene expression and cell cycle arrest mediated by transcription factor DMP1 is antagonized by D-type cyclins through a cyclin-dependent-kinase-independent mechanism. 948 76

Osteosarcomas often suffer mutations of the RB (retinoblastoma) gene, with resultant inactivation of the pRb protein. pRb is one component in a cell-cycle control pathway that includes the p16 (encoded by the CDKN2A gene) and cyclin-dependent kinase 4 (cdk4, encoded by the CDK4 gene) proteins. We therefore sought to determine whether the CDKN2A and CDK4 genes were altered in those osteosarcomas that lacked RB inactivation. Twenty-one osteosarcomas (2 low-grade and 19 high-grade) were evaluated for homozygous deletion of the CDKN2A gene, CDK4 amplification, and allelic loss of the RB gene, as well as for expression of p16 and pRb proteins. Five high-grade osteosarcomas showed loss of p16 expression; four of these had homozygous CDKN2A deletions, and the fifth had a probable deletion obscured by numerous nonneoplastic, p16-immunopositive multinucleated giant cells. Thus, p16 immunohistochemistry may provide a sensitive means for assessing CDKN2A status. Twelve tumors (including the two low-grade osteosarcomas) were immunopositive for pRb, and nine tumors were immunonegative for pRb. Of the five cases with CDKN2A/p16 alterations, none had allelic loss of the RB gene and all expressed pRb, suggesting that each of these tumors had an intact RB gene. None of the tumors showed CDK4 amplification. No alterations were detected in the two low-grade osteosarcomas. This study suggests that CDKN2A is a tumor suppressor inactivated in osteosarcomas that lack RB mutations and that the p16-pRb cell-cycle control pathway is deregulated in a large number of high-grade osteosarcomas.
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PMID:CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations. 966 76

Terminal differentiation of many cell lineages involves an exit from the mitotic cycle and entry into, and maintenance of, a permanent state of G1 arrest. We found that during terminal differentiation of mouse 3T3-L1 preadipocytes, the level of cyclin-dependent kinase 4 (CDK4) remained constant, but the subunit composition of the CDK4 complex underwent a dynamic rearrangement. As 3T3-L1 cells differentiated, the levels of cyclin D1 and cyclin D1-CDK4 complexes declined to negligible levels. Meanwhile, cyclins D2 and D3 levels and their associations with CDK4 increased transiently and persistently, respectively, with cyclin D3 becoming the predominant cyclin partner of CDK4 in mature adipocytes. At least five CDK inhibitors are expressed during the differentiation program of 3T3-L1 cells. Both p15INK4b and p16INK4a continuously declined to undetectable levels immediately after differentiation induction. p21 was transiently expressed during the exit of 3T3-L1 cells from mitotic clonal expansion and then decreased to undetectable levels in mature adipocytes. The level of p27KiP1 and p27-CDK4 complexes remain high during differentiation and in mature adipocytes. Distinctly, there is a remarkable induction of p18INK4c mRNA and protein that was not seen in the closely related nondifferentiating 3T3-C2 cell line, suggesting that p18 induction in 3T3-L1 cells is related to cell differentiation, not cell cycle arrest. The pRb kinase activity of cyclin D3 and CDK4 was not detected in quiescent 3T3-L1 cells and was then induced as the cells entered the mitotic clonal expansion phase. Unexpectedly, cyclin D3 and CDK4 pRb kinase activity remained high after 3T3-L1 cells completed their mitotic division and was still readily detectable in mature adipocytes. Our study reveals an active regulation, rather than passive inhibition, of CDK4 activity during adipocyte differentiation. Two central features of this complex regulation are switching of activating cyclin D subunits and concurrent binding by the p18 and p27 CDK inhibitors.
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PMID:Regulation of cyclin-dependent kinase 4 during adipogenesis involves switching of cyclin D subunits and concurrent binding of p18INK4c and p27Kip1. 971 77

Using a new inducible form of phosphatidylinositol 3-kinase (PI 3-kinase) we have found that PI 3-kinase activation has the following effects on cell growth and proliferation. (i) Activation of PI 3-kinase was sufficient to promote entry into S phase of the cell cycle within several hours. This was shown by activation of cyclin-dependent kinase 4 (Cdk4) and Cdk2 and by the induction of DNA synthesis. (ii) PI 3-kinase activation alone was not, however, sufficient to provide for progression through the entire cell cycle. Instead, prolonged activation of PI 3-kinase in the absence of serum stimulation resulted in apoptosis. It is possible that the cells undergo apoptosis because the PI 3-kinase-induced entry into the cell cycle is abnormal. For example, we found that the cyclin E-Cdk2 complex, which normally disappears after entry into S phase of the cell cycle, fails to be downregulated following induction by PI 3-kinase. (iii) Finally, we found that prolonged activation of PI 3-kinase in the presence of serum resulted in cellular changes that resemble those associated with oncogenic transformation. The cells reached high densities, were irregular and refractile in appearance, and formed colonies in soft agar. In contrast, neither PI 3-kinase nor serum stimulation alone could induce these changes. Our results suggest that activation of PI 3-kinase promotes anchorage-independent cell growth and entry into the cell cycle but does not abrogate the growth factor requirement for cell proliferation.
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PMID:Activation of phosphatidylinositol 3-kinase is sufficient for cell cycle entry and promotes cellular changes characteristic of oncogenic transformation. 974 87

Although it is known that calmodulin is involved in G1 progression, the calmodulin-dependent G1 events are not well understood. We have analyzed here the role of calmodulin in the activity, the expression, and the intracellular location of proteins involved in G1 progression. The addition of anti-calmodulin drugs to normal rat kidney cells in early G1 inhibited cyclin-dependent kinase 4 (Cdk4) and Cdk2 activities, as well as retinoblastoma protein phosphorylation. Protein levels of cdk4, cyclin D1, cyclin D2, cyclin E, p21, and p27 were not affected after CaM inhibition, whereas decreases in the amount of cyclin A and Cdc2 were observed. The decrease of Cdk4 activity was due neither to changes in its association to cyclin D1 nor to changes in the amount of p21 or p27 bound to cyclin D1-Cdk4 complexes. Calmodulin inhibition also produced a translocation of nuclear cyclin D1 and Cdk4 to the cytoplasm. This translocation could be responsible for the decreased Cdk4 activity upon calmodulin inhibition. Immunoprecipitation, calmodulin affinity chromatography, and direct binding experiments indicated that calmodulin associates with Cdk4 and cyclin D1 through a calmodulin-binding protein. The facts that Hsp90 interacts with Cdk4 and that its inhibition induced Cdk4 and cyclin D1 translocation to the cytoplasm point to Hsp90 as a good candidate for being the calmodulin-binding protein involved in the nuclear accumulation of Cdk4 and cyclin D1.
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PMID:Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1. 983

Transcription of rRNA genes by RNA polymerase I increases following serum stimulation of quiescent NIH 3T3 fibroblasts. To elucidate the mechanism underlying transcriptional activation during progression through the G1 phase of the cell cycle, we have analyzed the activity and phosphorylation pattern of the nucleolar transcription factor upstream binding factor (UBF). Using a combination of tryptic phosphopeptide mapping and site-directed mutagenesis, we have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro. The data demonstrate that UBF is regulated in a cell cycle-dependent manner and suggest a link between G1 cdks-cyclins, UBF phosphorylation and rDNA transcription activation.
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PMID:Phosphorylation by G1-specific cdk-cyclin complexes activates the nucleolar transcription factor UBF. 1020 52

Two regulators of the eukaryotic cell cycle, cell division cycle 2 (cdc2) and cyclin-dependent kinase 4 (cdk4), have been reported to be related to Alzheimer's disease (AD) pathology, and especially to hyperphosphorylated tau protein. Using well-characterized polyclonal antibodies which recognize the C termini of cdc2 kinase and cdk4, we examined by immunohistochemistry brain tissues from patients with non-neurological conditions, AD and cerebral infarction. Semiquantitative mRNA analysis by RT-PCR was also done using non-neurological and AD brains. In AD, as previously reported, the antibody to cdc2 showed positive staining of a few intracytoplasmic neurofibrillary tangles (NFTs). In addition, this antibody gave positive immunolabelling in astrocytes and capillaries in all brains studied. In both AD and cerebral infarct cases, the staining of astrocytes was more intense than in non-neurological brain tissue. In all cases, the antibodies to cdk4 showed positive immunolabelling in the nuclei of all cell types except neurons. In AD tissue, the antibody showed additional staining of neuronal nuclei and cytoplasm. In contrast to a previous report, we did not find positive labelling of NFTs with the anti-cdk4 antibody. In infarct areas, particularly strong nuclear staining in glial cells was seen. The relative levels of cdk4 mRNA in AD brains were higher than those in controls. These data suggest that cdc2 kinase appears in glial cells capable of cell division and may play a role in the regulation of amyloid precursor protein processing and NFT formation in neurons. As suggested in a report on rat brain, neuronal expression of cdk4 may reflect some pathological process in damaged cells in AD.
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PMID:Localization and expression of cdc2 and cdk4 in Alzheimer brain tissue. 1032 46

By crossing TG.AC v-Ha-ras and K6/ODC transgenic mice, we found previously that an activated ras and follicular ornithine decarboxylase (ODC) overexpression cooperate to generate spontaneous tumors in the skin. Cellular proliferation was dramatically increased in the K6/ODC transgenic skin, as evidenced by elevated proliferating cell nuclear antigen and Ki67 expression compared with nontransgenic littermates. Keratinocytes isolated from transgenic skin also displayed increased clonal growth. Paradoxically, expression of the growth inhibition-associated proteins p53, p21Waf1, p27Klp1, and Bax was increased with ODC overexpression in the skin. ODC overexpression did not affect cyclin D/cyclin-dependent kinase 4 (Cdk4)-dependent phosphorylation of retinoblastoma protein but stimulated cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity, with minimal effect on the levels of these proteins. Thus, ODC/polyamine-induced activation of cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity may cooperate with the ras induction of cyclin D/Cdk4/6-associated retinoblastoma protein phosphorylation to not only stimulate proliferation but ultimately contribute to tumor development.
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PMID:Effect of elevated levels of ornithine decarboxylase on cell cycle progression in skin. 1059 50

We analysed p16 gene alteration and p16, cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, cyclin D2, cyclin D3 and retinoblastoma protein (pRb) expression in ten normal endometriums (PE), 18 endometrial hyperplasias (EH) and 35 endometrial cancers (EC). Two of ten PE (20%), nine of 18 EH (50.0%) and 29 of 35 EC (82.9%) exhibited p16 nuclear staining. p16 expression was significantly higher in EC than EH (P = 0.0119). In the six p16 (-) EC, one was considered to have reduced gene dosage consistent with possible homozygous deletion of the CDKN2 gene and three had methylation in 5'CpG island in the promoter region of the p16 gene, whereas none showed such reduced gene dosage and four had methylation in the nine p16 (-) EH. Strong CDK4 staining was observed in 12 of 35 EC (34.3%) and one of 18 EH (5.6%). The strong expression of CDK4 was higher in EC than in EH (P = 0.0399). The expression of CDK4 was higher in EH than PE (P = 0.0054). The abnormalities of p16-cyclin D/CDK-pRb pathway were detected in 18 of 35 EC (51.4%). In conclusion, the expression of p16 and CDK4 may be an early event in the neoplastic transformation of endometrial cancer.
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PMID:The role of p16-cyclin d/CDK-pRb pathway in the tumorigenesis of endometrioid-type endometrial carcinoma. 1068 82

Neuronal death evoked by DNA damage requires cyclin-dependent kinase 4 (Cdk4) and 6 activity and is accompanied by elevation of cyclin D1-associated kinase activity. Because Cdk4/6 phosphorylates retinoblastoma protein (pRb) family members that then modulate the transcriptional activity of E2F/DP1 complexes, we examined the involvement of these components in DNA damage-evoked neuronal death. Camptothecin induced rapid pRb and p107 phosphorylation at a Cdk4/6 phosphorylation site followed by selective loss of Rb and p107. The CDK inhibitor flavopiridol suppressed pRb and p107 phosphorylation and loss, implicating CDK activity in these events. Moreover, the loss of pRb and p107 appeared to be mediated by caspases because it was blocked by general caspase inhibitors. The role of phosphorylation and pRb and p107 loss in the death pathway was indicated by observations that virally mediated expression of pRb mutated at sites of phosphorylation, including the Cdk4/6 site, inhibited death. Finally, expression of dominant-negative versions of DP1, known to compromise E2F transcriptional activity, protects cortical neurons from death induced by camptothecin and sympathetic neurons from death evoked by UV treatment. Taken together, these results implicate the CDK-pRb/E2F/DP pathway as a required element in the neuronal death evoked by DNA damage.
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PMID:Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. 1077 74


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