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)

We demonstrate in this paper that the G1 phase specific cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D- and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 specific cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The findings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.
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PMID:Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4. 939 49

Cyclin C, a putative G1 cyclin, was originally isolated through its ability to complement a Saccharomyces cerevisiae strain lacking the G1 cyclin gene CLN1-3. Unlike cyclins D1 and E, the other two G1 cyclins obtained by the same approach and subsequently shown to play important roles during the G1/S transition, there is thus far no evidence to support the hypothesis that cyclin C is indeed critical for the promotion of cell cycle progression. In BAF-B03 cells, an interleukin 3 (IL-3)-dependent murine pro-B-cell line, cyclin C gene mRNA was induced at the G1/S phase upon IL-3 stimulation and reached a maximal level in the S phase. Enforced expression of exogenous cyclin C in this cell line failed to alter its growth properties. In the present study, we examined whether cyclin C is capable of cooperating with the cytokine-responsive immediate-early gene products c-Myc and c-Fos in the promotion of cell proliferation. We found that cyclin C is able to cooperate functionally with c-Myc, but not c-Fos, to induce both BAF-B03 cell proliferation in a cytokine-independent fashion and the formation of cell clusters. Furthermore, cyclin C was primarily responsible for the induction of cdc2 gene expression. Our data define a novel role for cyclin C in the regulation of both the G1/S and G2/M phases of the cell cycle, and this effect appears to be independent of the activity of CDK8 in the control of transcription.
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PMID:A critical role for cyclin C in promotion of the hematopoietic cell cycle by cooperation with c-Myc. 958 84

Estrogen-induced progression through G1 phase of the cell cycle is preceded by increased expression of the G1-phase regulatory proteins c-Myc and cyclin D1. To investigate the potential contribution of these proteins to estrogen action, we derived clonal MCF-7 breast cancer cell lines in which c-Myc or cyclin D1 was expressed under the control of the metal-inducible metallothionein promoter. Inducible expression of either c-Myc or cyclin D1 was sufficient for S-phase entry in cells previously arrested in G1 phase by pretreatment with ICI 182780, a potent estrogen antagonist. c-Myc expression was not accompanied by increased cyclin D1 expression or Cdk4 activation, nor was cyclin D1 induction accompanied by increases in c-Myc. Expression of c-Myc or cyclin D1 was sufficient to activate cyclin E-Cdk2 by promoting the formation of high-molecular-weight complexes lacking the cyclin-dependent kinase inhibitor p21, as has been described, following estrogen treatment. Interestingly, this was accompanied by an association between active cyclin E-Cdk2 complexes and hyperphosphorylated p130, identifying a previously undefined role for p130 in estrogen action. These data provide evidence for distinct c-Myc and cyclin D1 pathways in estrogen-induced mitogenesis which converge on or prior to the formation of active cyclin E-Cdk2-p130 complexes and loss of inactive cyclin E-Cdk2-p21 complexes, indicating a physiologically relevant role for the cyclin E binding motifs shared by p130 and p21.
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PMID:c-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. 967 59

Estrogens are potent mitogens in a number of target tissues including the mammary gland where they play a pivotal role in the development and progression of mammary carcinoma. The demonstration that estrogen-induced mitogenesis is associated with the recruitment of non-cycling, G0, cells into the cell cycle and an increased rate of progression through G1 phase, has focused attention on the estrogenic regulation of molecules with a known role in the control of G1-S phase progression. These experiments provide compelling evidence that estrogens regulate the expression and function of c-Myc and cyclin D1 and activate cyclin E-Cdk2 complexes, all of which are rate limiting for progression from G1 to S phase. Furthermore, these studies reveal a novel mechanism of activation of cyclin E-Cdk2 complexes whereby estrogens promote the formation of high molecular weight complexes lacking the CDK inhibitor p21. Inducible expression of either c-Myc or cyclin D1 can mimic the effects of estrogen in activating the cyclin E-Cdk2 complexes and promoting S phase entry, providing evidence for distinct c-Myc and cyclin D1 pathways in estrogen-induced mitogenesis which converge on the activation of cyclin E-Cdk2. These data provide new mechanistic insights into the known mitogenic effects of estrogens and identify potential downstream targets that contribute to their role in oncogenesis.
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PMID:Estrogen regulation of cell cycle progression in breast cancer cells. 969 70

We show here that the adenovirus E1A oncoprotein prevents growth arrest by the CDK2 inhibitor p27(Kip1) (p27) in rodent fibroblasts. However, E1A neither binds p27 nor prevents inhibition of CDK2 complexes in vivo. In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3. Moreover, E1A allows cell proliferation in the presence of supraphysiological p27 levels, while c-Myc, known to induce a cellular p27-inhibitory activity, is only effective against physiological p27 concentrations. E1A also bypasses G1 arrest by roscovitine, a chemical inhibitor of CDK2. Altogether, these findings imply that E1A can act downstream of p27 and CDK2. Retinoblastoma (pRb)-family proteins are known CDK substrates; as expected, association of E1A with these proteins (but not with p300/CBP) is required for E1A to prevent growth arrest by either p27 or the CDK4/6 inhibitor p16(INK4a). Bypassing CDK2 inhibition requires an additional function of E1A: the mutant E1A Delta26-35 does not overcome p27-induced arrest, while it binds pRb-family proteins, prevents p16-induced arrest, and alleviates pRb-mediated repression of E2F-1 transcriptional activity (although E1A Delta26-35 fails to restore expression of E2F-regulated genes in p27-arrested cells). We propose that besides the pRb family, E1A targets specific effector(s) of CDK2 in G1-S control.
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PMID:A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1). 977 42

The protein Mad1 heterodimerizes with Max to form an E-box binding complex able to interfere with the transcriptional and transforming activities of c-Myc. Downregulation of c-Myc accompanied by induction of Mad1 upon differentiation has fueled the notion that Mad1 may play a role in the cessation of proliferation associated with the differentiation process. Since studies on Mad1 expression have so far been limited to cells undergoing differentiation, it was of interest to examine Mad1 expression in a cell system unable to differentiate. To do so, we utilized the leukemia-derived B-precursor cell line, Reh, and studied the expressions of Mad1, c-Myc, Mxil, and Max during cAMP-mediated growth inhibition of these cells. Thus, the adenylate cyclase activator forskolin induced growth inhibition of the cells in the G1 phase of the cell cycle. This growth inhibition was associated with transient increased expression of Mad1 concomitant with transient downregulation of c-Myc. The Mad1 protein levels essentially paralleled those of mRNA, with peak levels at 4 h of forskolin treatment. By coimmunoprecipitation we detected increased binding of Mad1 to Max in forskolin-treated cells, indicating that the changes in Mad1 protein levels had functional implications. By continually treating Reh cells with forskolin for 72 h, we observed a sustained elevated expression of Mad1 concomitant with downregulated c-Myc expression, still without changing the differentiation profile of the Reh cells. Interestingly, we showed that other known cell cycle regulatory proteins also were transiently regulated by forskolin. To this extent, following forskolin treatment of Reh cells, cyclin E-cdk2 activity was transiently reduced concomitant with dephosphorylation of pRB. We suggest that the early changes in Mad1 and the cell cycle regulatory proteins initiate a chain of events resulting in permanent growth arrest. Thus, the increased expression of Mad1 in the absence of differentiation indicates that Mad1 expression in Reh cells is linked to growth arrest per se.
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PMID:Mad1 expression in the absence of differentiation: effect of cAMP on the B-lymphoid cell line Reh. 988 93

Confluent 3T3-L1 preadipocytes differentiate to adipocytes in the presence of insulin, dexamethasone, and isobutylmethylxanthine (IDI). A transient increase of DNA synthesis is induced in 3T3-L1 cells 18 h after addition of IDI, followed by an arrest in the G1 phase of the cell cycle. Growth arrested cells express the proto-oncogene c-myc and the gene for the CCAAT/enhancer binding protein (C/EBPalpha) between day 2 and 5. While c-Myc is strongly implicated in cell proliferation, C/EBPalpha: is a differentiation-specific transcription factor with antiproliferative activity. Here we have characterized the cell cycle arrest in differentiating 3T3-L1 cells. Arrested cells express the Cdk inhibitors p21 and p27, but, at the same time, show hyperphosphorylation of Rb and expression of the E2F-regulated thymidine kinase gene. The addition of new serum to arrested cells resulted in cyclin A expression and Cdk2 activity, but not in DNA synthesis. Simian virus 40 large tumor antigen (LTAg) is a potent mitogen. The mutant LTAg-K1, deficient in binding of pocket proteins and unable to induce DNA synthesis in serum-starved 3T3-L1 cells, efficiently induced DNA synthesis in differentiating 3T3-L1 cells. This indicates that pocket proteins are probably not involved in the control of the cell cycle arrest during 3T3-L1 cell differentiation. Our data suggest that the differentiation-specific cell cycle block in 3T3-L1 cells is resistant to high levels of c-Myc, inactivation of pocket proteins, upregulation of cyclin A levels, and Cdk2 activation, but can be abolished by a function of LTAg that is independent of binding to pocket proteins.
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PMID:Analysis of cell cycle arrest in adipocyte differentiation. 992 2

Tumor necrosis factor (TNFs) have been shown to be synthesized by ovarian carcinomas, and may therefore affect tumor cells in an autocrine manner. Therefore, we investigated the effects of recombinant TNFs on ovarian carcinoma cells N.1 and examined expression of the proto-oncogenes c-myc and cdc25A which are known to play a prominent role in apoptosis. TNFalpha elicited apoptosis in N.1 cells within 72 h which was shown by typical morphological changes, DNA fragmentation and signature type cleavage of poly(ADP-ribose) polymerase into a 89 kDa proteolytic peptide. TNFalpha-induced apoptosis was accompanied by constitutive c-Myc expression, although the mRNA level of phosphatase cdc25A was suppressed within 24 h of TNFalpha treatment and the protein level decreased after 48 h. Cdc25A tyrosine phosphatase is an activator of the cdk2-cyclin E complex which allows for cell cycle progression. As expected, we found TNFalpha-mediated Cdc25A down-regulation to inhibit Cdk2 activity. Cdc25A suppression was related to TNFalpha-induced apoptosis but not to a TNFalpha-induced G0 arrest because cyclin D1 expression was unaffected and the gene gas6 (growth arrest specific 6) was not induced. Arresting cells by treatment with genistein prevented TNFalpha-triggered apoptosis and inhibited c-myc expression. TNFalpha-induced apoptosis is not accompanied by cell cycle arrest which may be due to constitutive c-Myc expression, although Cdc25A and Cdk2 activity is also down-regulated. High c-Myc and low Cdc25A activity might present conflicting signals to the cell cycle machinery which are incompatible with cell survival.
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PMID:TNFalpha-mediated cell death is independent of cdc25A. 1020 May 35

NF-kappaB is an inducible transcription factor, which is regulated by interaction with inhibitory IkappaB proteins. Previous studies linked the activity of NF-kappaB to the proliferative state of the cell. Here we have analysed the function of NF-kappaB in the cell cycle. Inhibition of NF-kappaB in HeLa cells by stable overexpression of a transdominant negative IkappaB-alpha protein reduced cell growth. A kinetic analysis of the cell cycle revealed a retarded G1/S transition. The IkappaB-alpha overexpressing cell clones showed a decreased percentage of cells in the S phase and an impaired incorporation of bromodeoxyuridine (BrdU). The amounts of cyclins A, B1, D1, D3, and E were unchanged, but the G1-specific proteins cyclin D2 and cdk2 were strongly elevated in the IkappaB-alpha overexpressing cell clones. These cell clones also displayed an increase in cyclin D1-dependent kinase activity, pointing to a cell cycle arrest at the late G1 phase. IkappaB-alpha overexpression crosstalked to cell cycle checkpoints via a reduction of transcription factor p53 and elevation of p21WAF. Surprisingly, the IkappaB-alpha overexpressing cells showed an enrichment of c-Myc in the nucleoli, although the total amount of c-Myc protein was unchanged. These experiments identify an important contribution of the NF-kappaB/IkappaB system for the growth of HeLa cells.
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PMID:Repression of NF-kappaB impairs HeLa cell proliferation by functional interference with cell cycle checkpoint regulators. 1035 27

c-myc is a cellular proto-oncogene associated with a variety of human cancers and is strongly implicated in the control of cellular proliferation, programmed cell death, and differentiation. We have previously reported the first isolation of a c-myc-null cell line. Loss of c-Myc causes a profound growth defect manifested by the lengthening of both the G1 and G2 phases of the cell cycle. To gain a clearer understanding of the role of c-Myc in cellular proliferation, we have performed a comprehensive analysis of the components that regulate cell cycle progression. The largest defect observed in c-myc-/- cells is a 12-fold reduction in the activity of cyclin D1-Cdk4 and -Cdk6 complexes during the G0-to-S transition. Downstream events, such as activation of cyclin E-Cdk2 and cyclin A-Cdk2 complexes, are delayed and reduced in magnitude. However, it is clear that c-Myc affects the cell cycle at multiple independent points, because restoration of the Cdk4 and -6 defect does not significantly increase growth rate. In exponentially cycling cells the absence of c-Myc reduces coordinately the activities of all cyclin-cyclin-dependent kinase complexes. An analysis of cyclin-dependent kinase complex regulators revealed increased expression of p27(KIP1) and decreased expression of Cdk7 in c-myc-/- cells. We propose that c-Myc functions as a crucial link in the coordinate adjustment of growth rate to environmental conditions.
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PMID:c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. 1037 16


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