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)

E2F transcription factors regulate the expression of a number of genes important in cell proliferation, particularly those involved in progression through G1 and into the S-phase of the cell cycle. The activity of E2F factors is regulated through association with the retinoblastoma tumor suppressor protein (Rb) and the other pocket proteins, p107 and p130. Binding of Rb, p107 or p130 converts E2F factors from transcriptional activators to transcriptional repressors. The interplay among G1 cyclins (D-type cyclins and cyclin E), cyclin-dependent kinases (cdk4, 6, and 2), cdk inhibitors, and protein phosphatases determines the phosphorylation state of the pocket proteins which in turn regulates the ability of the pocket proteins to complex with E2F. E2F activity is further regulated through direct interactions with other factors, such cyclin A, Sp1, p53 and the ubiquitin-proteasome pathway. Deregulated expression of E2F family member genes has been shown to induce both inappropriate S phase entry and apoptosis. An important role for E2F in the development of cancer is suggested by the finding that in most human neoplasias, genetic or epigenetic alterations occur that ultimately result in the deregulation of E2F-dependent transcription. This review will highlight recent findings on the specific roles of the individual E2F species in regulating transcription, proliferation and apoptosis, and discuss the growing link between E2F and cancer.
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PMID:Role of E2F in cell cycle control and cancer. 955 98

The mammalian cell cycle engine, which is composed of cyclin/CDK holoenzymes, controls the progression throughout the cell cycle by regulating, at least in part, the transcription of two types of genes: genes whose protein products are required for DNA metabolism and genes whose protein products are involved in cell cycle control. Among the targets of cyclin/CDKs, there is a family of negative growth regulators collectively known as pocket proteins. This family of pocket proteins includes the product of the retinoblastoma tumor suppressor gene, pRB and the functionally and structurally related proteins p107 and p130. In this review, the mechanisms by which pocket proteins are thought to regulate cell growth and differentiation are discussed.
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PMID:pRB, p107 and p130 as transcriptional regulators: role in cell growth and differentiation. 958 Feb 69

It has previously been shown that following viral infection, Ad5 E1A induces cell cycle progression of quiescent rodent cells, leading to DNA synthesis and mitosis. Here we have examined the effect of Ad12 E1A on the cell cycle characteristics of human cells. Human tumor (A549, KB, and HeLa) cells were infected with Ad12 d/620, a mutant virus which has a lesion in the E1B gene and essentially expresses only E1A. These infected cells progressed from being largely in G1 into S phase, where they arrested. Even up to 96 h postinfection (p.i.) the cells remained blocked in S phase. DNA synthesis did, however, proceed in Ad12 d/620-infected cells, giving rise to multiple copies of cellular DNA. Similar results were obtained when primary human skin fibroblasts were infected, although the polyploidy was less marked. The expression of cyclins A, B1, and E in the tumor cells increased appreciably in response to E1A. In contrast, there was a dramatic reduction in the levels of cyclin D1 and D3. Increases in cyclin D1 expression could be detected at very late times p.i. In those cell lines expressing low levels of cdc2 and cdk2 an appreciable increase in expression was seen soon after Ad12 E1A could be detected. The elevated levels of cyclins A, B1, and E were associated with increased protein kinase activity directed against histone H1. An increase in cyclin D1-associated kinase activity against Rb1 was also observed at late times. This deregulation of the cell cycle was not solely dependent on E1A inactivation of Rb, since similar effects were seen in Ad12 d/620-infected retinoblastoma (Y-79) cells, implicating p107 and p130 in E1A-mediated changes in cell cycle progression. We propose that the E1A-induced levels of cyclins A, B1, and E by Ad12 E1A in human cells may lead to an uncoupling of S phase from cell cycle progression.
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PMID:Human cells arrest in S phase in response to adenovirus 12 E1A. 960 4

Taken together, the available data appear to be consistent with a model in which Myc proteins function downstream of D-type cyclins and synergize with E2F proteins in the activation of the cyclin E/cdk2 kinase. This view of Myc proteins appears strikingly similar to established models for the E2F/DP family of proteins. However, it should be noted that there are clear differences and several predictions of such a model that have been critically tested for E2F proteins are still untested for Myc in this model. First, it appears that at least some target genes of Myc implicated in this process are still unknown; second, clear data from knockout cells that link p107 to Myc function are missing; and third, we are not aware of studies of tumour samples that clarify whether mutations in myc genes relieve the requirement for mutations in the cyclin D/p16 pathway.
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PMID:Control of cell proliferation by Myc proteins. 967 Mar 24

GATA-1 is a tissue-specific DNA-binding protein containing two zinc-finger-like domains. It is expressed predominantly in erythrocytes. Consensus binding sites for GATA-1 have been found in the regulatory elements of all erythroid-specific genes examined. GATA-1 protein is required for erythroid differentiation beyond the proerythroblast stage. In this paper, we demonstrate that the overexpression of GATA-1 in murine erythroleukaemia (MEL) cells alleviates DMSO-induced terminal erythroid differentiation. Hence, there is no induction of globin gene transcription and the cells do not arrest in the G1 phase of the cell cycle. Furthermore, we demonstrate that expression of GATA-1 in non-transformed erythroid precursors also affects their proliferative capacity and terminal differentiation, as assayed by adult globin gene transcription. To gain insight into the mechanism of this effect, we studied the levels and activities of regulators of cell-cycle progression during DMSO-induced differentiation. A decrease in cyclin D-dependent kinase activity was observed during the induction of both control and GATA-1-overexpressing MEL cells. However, cyclin E-dependent kinase activity decreased more than 20-fold in control but less than 2-fold in GATA-1-overexpressing MEL cells upon induction. Thus GATA-1 may exert its effects by regulating cyclin E-dependent kinase activity. We also show that GATA-1 binds to the retinoblastoma protein in vitro, but not to the related protein p107, which may indicate that GATA-1 interacts directly with specific members of the cell-cycle machinery in vivo. We conclude that GATA-1 regulates cell fate, in terms of differentiation or proliferation, by affecting the cell-cycle apparatus.
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PMID:The level of the tissue-specific factor GATA-1 affects the cell-cycle machinery. 968 Mar 25

The retinoblastoma (pRB) family of proteins includes three proteins known to suppress growth of mammalian cells. Previously we had found that growth suppression by two of these proteins, p107 and p130, could result from the inhibition of associated cyclin-dependent kinases (cdks). One important unresolved issue, however, is the mechanism through which inhibition occurs. Here we present in vivo and in vitro evidence to suggest that p107 is a bona fide inhibitor of both cyclin A-cdk2 and cyclin E-cdk2 that exhibits an inhibitory constant (Ki) comparable to that of the cdk inhibitor p21/WAF1. In contrast, pRB is unable to inhibit cdks. Further reminiscent of p21, a second cyclin-binding site was mapped to the amino-terminal portions of p107 and p130. This amino-terminal domain is capable of inhibiting cyclin-cdk2 complexes, although it is not a potent substrate for these kinases. In contrast, a carboxy-terminal fragment of p107 that contains the previously identified cyclin-binding domain serves as an excellent kinase substrate although it is unable to inhibit either kinase. Clustered point mutations suggest that the amino-terminal domain is functionally important for cyclin binding and growth suppression. Moreover, peptides spanning the cyclin-binding region are capable of interfering with p107 binding to cyclin-cdk2 complexes and kinase inhibition. Our ability to distinguish between p107 and p130 as inhibitors rather than simple substrates suggests that these proteins may represent true inhibitors of cdks.
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PMID:Dual cyclin-binding domains are required for p107 to function as a kinase inhibitor. 971 Jun 22

We previously demonstrated that P16Ink4a (p16) expression in p16-deficient U343 astrocytoma cells causes a G1 cell cycle arrest, profound changes in cytoskeletal proteins and alterations in expression and activity of the pRB and E2F family proteins. We examine here the effects of expressing wild type or mutant versions of the downstream targets of p16 in U343 astrocytomas. We first attempted to block proliferation of U343 cells using the dominant mutant of pRB, deltap34. Expression of this mutant in the human osteosarcoma, SAOS-2, potently blocked proliferation but did not affect the cell cycle of U343 cells. We next showed that expression of E2F-1, E2F-2, E2F-3 and E2F-4 are each able to overcome this p16-dependent cell cycle arrest but exhibit distinct biological activities. Adenoviral-mediated expression of E2F-1, E2F-2, E2F-3, or E2F-4 overcame the p16-dependent cell cycle block and induced alterations in cell morphology. E2F-5, only in conjunction with DP1, promoted cell cycle progression. For both E2F-1 and E2F-2, but not E2F-3 or E2F-5/DP1, cell cycle re-entry was associated with almost quantitative cell death. Only small numbers of dying cells were observed in E2F-4-expressing cultures. Expression of the different E2F's altered the expression of distinct sets of cell cycle regulatory proteins. E2F-1 induced endogenous E2F-4 expression and also caused an increase in pRB, p107 and cyclin E levels. Expression of E2F-4 caused a weak increase in E2F-1 levels but also strongly induced pRB, p107, p130 and cyclin E. However, E2F-1 and E2F-4 clearly regulate expression of distinct genes, demonstrated when E2F-4 caused a threefold increase in the levels of cdk2 whereas E2F-1 failed to increase in this cyclin dependent kinase. Similarly, expression of E2F-1 or E2F-2 were shown to have distinct effects on the expression of cdk2, cyclin E and pRB despite both of these closely related E2F-family members potently inducing cell death. Thus, E2F-1, E2F-2, E2F-3 and E2F-4 are able to overcome the p16-dependent proliferative block in U343 astrocytoma cells. While overcoming this cell cycle block, each of the E2F's uniquely affect the expression of a number of cell cycle regulatory proteins and have distinct abilities to promote cell death.
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PMID:The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells. 978 3

Retinoblastoma (Rb) protein has been implicated in the control of cell proliferation and malignant transformation in different cell types. To analyze its role as a promoter of cell growth arrest during development, we have studied the temporal pattern of Rb expression and its association with E2F-1 during embryogenesis of the quail neuroretina. During development of this neural organ, most cells stop dividing and begin to differentiate at embryonic days E6 and E7, as indicated by the decline of cyclin-dependent kinase cdk2 and by an increased level of cdk5. At this stage, we observed a shift of hyperphosphorylated Rb protein to its hypophosphorylated form as well as a decrease of the total level of Rb. The Rb-related protein, p107, is also progressively down-regulated from the E7 stage onwards. P130 levels, on the other hand, actually increase. Moreover, cell cycle exit at E6-E7 is characterized by a sudden and transient rise of the E2F-1/RB complex followed by the appearance of the E2F-4/p130 complex starting at E8. Conversely, expression of adenovirus E1A protein in E6 neuroretina cells leads to a dissociation of E2F-1/Rb complex and suppression of cell growth arrest and differentiation. This suggests that cell cycle exit and re-entry may depend on Rb/E2F-1 interaction. Although the rate of Rb synthesis declines in postmitotic cells, as suggested by in vivo metabolic labeling of the Rb protein, the level of the Rb transcript remains
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PMID:Transient accumulation of retinoblastoma/E2F-1 protein complexes correlates with the onset of neuronal differentiation in the developing quail neural retina. 979 Apr 97

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

The response of the uterine epithelium to female sex steroid hormones provides an excellent model to study cell proliferation in vivo since both stimulation and inhibition of cell proliferation can be studied. Thus, when administered to ovariectomized adult mice 17beta-estradiol (E2) stimulates a synchronized wave of DNA synthesis and cell division in the epithelial cells, while pretreatment with progesterone (P4) completely inhibits this E2-induced cell proliferation. Using a simple method to isolate the uterine epithelium with high purity, we have shown that E2 treatment induces a relocalization of cyclin D1 and, to a lesser extent, cdk4 from the cytoplasm into the nucleus and results in the orderly activation of cyclin E- and cyclin A-cdk2 kinases and hyperphosphorylation of pRb and p107. P4 pretreatment did not alter overall levels of cyclin D1, cdk4, or cdk6 nor their associated kinase activities but instead inhibited the E2-induced nuclear localization of cyclin D1 to below the control level and, to a lesser extent, nuclear cdk4 levels, with a consequent inhibition of pRb and p107 phosphorylation. In addition, it abrogated E2-induced cyclin E-cdk2 activation by dephosphorylation of cdk2, followed by inhibition of cyclin A expression and consequently of cyclin A-cdk2 kinase activity and further inhibition of phosphorylation of pRb and p107. P4 is used therapeutically to oppose the effect of E2 during hormone replacement therapy and in the treatment of uterine adenocarcinoma. This study showing a novel mechanism of cell cycle inhibition by P4 may provide the basis for the development of new antiestrogens.
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PMID:Progesterone inhibits estrogen-induced cyclin D1 and cdk4 nuclear translocation, cyclin E- and cyclin A-cdk2 kinase activation, and cell proliferation in uterine epithelial cells in mice. 1002 12


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