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)

Human myeloid leukemia cells (i.e., HL-60, U937, THP-1) which are induced to differentiate along the monocytic pathway by 12-O-tetradecanoylphorbol-13-acetate (TPA), revert back to the undifferentiated phenotype after 3 to 4 weeks. During this differentiation and retrodifferentiation process the cells obviously establish a distinct sequence of biological processes which is integrally regulated to simultaneously control differentiation and cell growth. Thus, induction of monocytic markers by TPA is associated with a down-regulation of cell cycle genes and cessation of proliferation. In particular, crosstalk between the TPA-induced translocation of protein kinase C (PKC) and the activation of transcription factors, especially AP-1, enhances the expression of genes associated with the monocytic phenotype. This is accompanied by induction of intermediate filament proteins, surface glycoproteins, changes in membrane properties and intracellular metabolism. In parallel, the cells cease to divide, and genes associated with cell cycle progression including cdc2, cyclins, cdc25, and histones are down-regulated. Although signals responsible for arrested cell growth remain unclear, there are several control mechanisms regarding cell cycle genes and differentiation parameters (for a review, see Nigg, E. A., Seminars in Cell Biol., 2, 262-270, 1991). For example, activated p34cdc2 kinase is involved in lamina disassembly by direct phosphorylation of lamin proteins which may contribute to nuclear envelope breakdown during mitosis (Enoch, T., M. Peter, P. Nurse, J. Cell Biol. 112, 797-807 (1991)). Moreover, endomembrane traffic is arrested by a cdc2-like kinase probably via phosphorylation of members of the rab protein family which contributes to vesiculation and membrane transport by hydrolyzing GTP (Tuomikoski, T., et al., Nature 342, 942-945 (1989)). Although there are several reports on a possible feedback control between differentiation and cell cycle, including phosphorylation of cyclins and activation of a ubiquitin-dependent proteolytic degradation, signaling pathways and possible mechanisms for retrodifferentiation and reentry into the cell cycle remain unclear. While some terminally differentiated cells are committed to die, the major part of the differentiated monocytic population undergoes retrodifferentiation. All cellular signals characterized so far are reverted during retrodifferentiation: Redistribution of PKC and down-regulation of c-fos and c-jun contribute to an interruption of the differentiation-associated transsignaling cascade. Thus, down-regulation of markers associated with monocytic differentiation in combination with metabolic changes restore the original cell phenotype. At the same time cell cycle genes are up-regulated, and the cells regain proliferative capacity. Finally, retrodifferentiated and untreated control cells demonstrate indistinguishable properties.
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PMID:Retrodifferentiation--an alternative biological pathway in human leukemia cells. 164 56

The pancreatic cell line beta TC1, established from insulinomas of transgenic mice carrying a hybrid insulin-promoted large T antigen gene, has retained several characteristics of normal cells, including the insulin content and inducibility of insulin secreting by glucose. We show here that the growth of beta TC1 cells is arrested in low serum-concentration medium. Cells exposed for three days to 0.25% fetal calf serum ceased to incorporate [3H]thymidine but were still able to resume the cell division cycle upon addition of serum. In this cell line, we have determined by cytofluorometry the cell cycle kinetic parameters to be of 21 h, 10 h 30 min and 12 h for the G1, S and G2/M phases, respectively. Quiescent beta TC1 cells constitutively expressed the protooncogene c-jun that codes for the transcriptional factor AP1, as well as cdc2, another cell cycle-related gene. A large transient increase in the expression of the c-fos gene was obtained rapidly, 30 min after addition of serum and a similar increase in c-jun expression after one hour. Expression of the cdc2 gene was also enhanced to a lesser extent. The same effects were also observed in the presence of cycloheximide, thus proving that the expression of these three genes is directly stimulated by serum growth factors. Consequently, quiescent beta TC1 cells provide a good model for studying the short- and long-term effects of growth factors on Beta-cell proliferation.
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PMID:Cell cycle and gene expression in the insulin producing pancreatic cell line beta TC1. 170 44

HLA class I antigens seem to be involved in the proliferative response of PHA-activated human T-lymphocytes. We have previously reported that the treatment of PHA-activated peripheral blood mononuclear cells (PBMC) with an anti-HLA class I monoclonal antibody, 01.65, (i) inhibits the tritiated thymidine incorporation, (ii) inactivates cytosolic protein kinase C (PKC) and (iii) causes an increase in the duration of the cell cycle. Northern Blot kinetic analysis of c-fos, c-myc, cdc2, IL-2R, c-myb, ODC, TK and H3, from 10 minutes to 120 hours, was performed in MAb 01.65 treated cultures. We found that the expression of four genes (c-myc, IL-2R, cdc2 and TK) was depressed 24 hours after PHA stimulation.
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PMID:Molecular analysis of cell cycle-related gene expression in anti-HLA class I monoclonal antibody (01.65) treated PHA-activated human T-lymphocytes. 177 40

Overexpression of c-Fos/AP-1 augments proliferation of splenic B cells stimulated with lipopolysaccharide (LPS). To elucidate mechanisms of the augmentation by c-Fos/AP-1, a cell cycle of the LPS-activated B cells from c-fos transgenic mice was analyzed. Cell cycle progression into the S phase was accelerated in the c-fos B cells. Expression of genes related to the cell cycle progression was examined in these B cells. Amount of cyclin D3 and cdk4 mRNA increased in the c-fos B cells at 6 h earlier than that in the control B cells, indicating that the kinetics of these mRNA expressions correlate with the acceleration of cell cycle progression. Furthermore, cyclin D1 and cyclin E mRNA were detected in the c-fos B cells but not in the control B cells. These results indicate that deregulated c-Fos/AP-1 modulates expression of the cyclin and the cdk gene in splenic B cells stimulated with LPS. These modulations may accelerate cell cycle progression and augment proliferation of the B cells.
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PMID:Deregulated c-Fos/AP-1 modulates expression of the cyclin and the cdk gene in splenic B cells stimulated with lipopolysaccharide. 754 12

Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are arrested with G1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c-fos. Later in G1, they uniformly fail to express late G1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin-dependent kinase inhibitor whose levels are also elevated in cells arrested in G1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactive the cell cycle machinery.
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PMID:Origins of G1 arrest in senescent human fibroblasts. 757 95

The proto-oncogene c-fos is known to be an important positive regulator of cell growth and notably of the G0/G1 transition. However, we observed that v-fos or c-fos-transformed rat-1 fibroblasts paradoxically had a low growth rate as compared to control untransformed rat-1 cells. We determined that this slow growth mainly reflects an increase of the G1 phase of the cell cycle (up to fourfold). In addition, the G0 --> S progression of serum-starved fos-expressing rat-1 cells refed with serum was found to be also delayed as compared to rat-1 cells. The delayed G0 --> S progression in fos-expressing cells was accompanied by the inappropriate levels or kinetics of expression of several cell cycle-regulated genes (cyclin D1, cdc2, cdk2, cdk4 and rb). Furthermore, a clear uncoupling of the pRb hyperphosphorylation with the entry into S phase was found in these fos-expressing rat-1 cells. Interestingly, the effect of the Fos proteins on the cell cycle was independent of the fos transforming pathway, indicating that the effector genes for Fos proteins are likely to be different for each process. In conclusion, our results indicate that Fos proteins may act as negative regulators of cell growth in some cell types, independently of the fos transforming pathway.
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PMID:Fos proteins can act as negative regulators of cell growth independently of the fos transforming pathway. 763 Jun 29

Density-arrested quiescent murine Balb/c-3T3 cells are dependent upon growth factors for their survival. Withdrawal of serum from their medium induces rapid cell death, the mechanism of which is not yet fully understood. We have studied the effect of serum deprivation on density-inhibited quiescent Swiss 3T3 cells and found that they undergo rapid cell death upon total withdrawal of serum. The nature of this cell death is similar to apoptosis, as shown by cellular and nuclear morphology and DNA fragmentation into oligonucleosomal fragments. Investigating the regulation of early cell-cycle genes during this process, we found that c-myc, c-jun, c-fos, and cdc2 protein presence is induced after serum deprivation, when the phosphorylated form of the RB protein also appears. The upregulation of these genes' protein products is coupled with the appearance of PCNA, a proliferation-specific nuclear antigen, as well as significant incorporation of BrdU, which may reflect DNA repair activity; in situ analysis shows that BrdU-positive cells are also positive for DNA fragmentation. These results suggest that en route to apoptosis, cells undergo events typical of early cell-cycle traverse by expressing early G1 genes and may even experience the late G1/S phase boundary, as shown by the presence of PCNA. However, the demonstrated ability of these cells to traverse the G1 phase of the cell cycle seems to be an abortive event, since they die shortly afterwards.
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PMID:Cells en route to apoptosis are characterized by the upregulation of c-fos, c-myc, c-jun, cdc2, and RB phosphorylation, resembling events of early cell-cycle traverse. 767 22

Proliferating cells characteristically undergo programmed (i.e. apoptotic) death if their progression through the cell cycle is sufficiently perturbed. To determine whether androgen ablation-induced programmed death of prostatic glandular cells involves apoptosis triggered by recruitment of nonproliferating cells into a perturbed cell cycle, rat ventral prostates were assessed temporally after castration for several stereotypical molecular stigmata of entry into the proliferative cell cycle. Northern blot analysis was used to assess levels of transcripts from genes characteristically activated 1) during the transition from quiescence (G(0)) into G1 of the proliferative cell cycle (cyclin-D1 and cyclin-C), 2) during the transition from G1 to S (cyclin-E, cdk2, thymidine kinase, and H4-histone), and 3) during progression through S (cyclin-A). Although levels of each of these transcripts increased as expected in prostatic glandular epithelial cells stimulated to proliferate by the administration of exogenous androgen to previously castrated rats, levels of the same transcripts decreased in prostatic glandular cells induced to undergo apoptosis after androgen withdrawal. Northern and Western blot analyses also demonstrated that there was no increase in prostatic p53 messenger RNA or protein content per cell after androgen ablation. Likewise, after castration, there was no enhanced prostatic expression of the WAF1/CIP1 gene, a gene whose expression is known to be induced in both a p53-dependent and -independent manner during recruitment from G0 into G1. In addition, androgen ablation-induced apoptosis of prostatic glandular cells was not accompanied by retinoblastoma protein phosphorylation, which is characteristic of progression into late G1. Nuclear run-on assays demonstrated that there was no increase in the prostatic rate of transcription of the c-myc and c-fos genes after castration. These results demonstrate that prostatic glandular cells undergo programmed death in G(0) without recruitment into the G1 phase of a defective cell cycle, and that an increase in p53 protein or its function is not involved in this death process.
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PMID:Androgen ablation-induced programmed death of prostatic glandular cells does not involve recruitment into a defective cell cycle or p53 induction. 772 Jun 36

tsJT16 is a cell-cycle temperature-sensitive (ts) mutant derived from rat fibroblasts whose functional defect appears soon after the growth stimulation from G0 phase. In addition to c-fos, c-myc and ornithine decarboxylase gene, 7 primarily inducible genes, c-jun, KC, JE, 2F1, 2A9, egr-1, and egr-2, were further shown to be expressed after serum stimulation at both permissive and nonpermissive temperatures. However, expression of secondarily inducible genes, cyclin D1 and D3 and cdk2, was ts and was cycloheximide sensitive. Expression of cyclin C was not inhibited by cycloheximide but it was ts. Failure in expression of G1 cyclins and Cdk2 is suggested to be a causal event for inability of growth induction of tsJT16 at the nonpermissive temperature.
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PMID:tsJT16, a cell cycle ts mutant of rat fibroblast defective in early G0/G1 transition, fails to induce G1-cyclin and cdk2 genes after serum stimulation at the nonpermissive temperature. 785 Aug 96

The uterine content of c-fos protein, cyclin B1 (cell cycle protein) and cdc2 p34(cyclin-dependent kinase) in immature and mature rats was determined using the enhanced chemiluminescence(ECL) western blot method. Cyclin B1 was found predominantly in immature rat uterus and cdc2 p34 only in mature rat uterus. Several isoforms of c-fos oncogene protein were present in both mature and immature rat uteri. An additional immunoreactive c-fos protein with an estimated molecular weight of 28 kDa was found in mature rat uterus and was missing in immature uterus. Uteri from ovariectomized rats treated with estrogen and/or ICI 182,780, an antiestrogen, were analyzed by ECL western blot. cdc2 p34 and the c-fos 28 kDa protein were found in estradiol-treated rat uteri and were not detected in uteri of control and ICI 182,780-treated animals; whereas Cyclin B1 was absent in uteri from control and estradiol-treated ovariectomized animals. ICI 182,780 administered to estradiol-treated ovariectomized rats blocked the induction of cdc2 p34 and the c-fos 28 kDa protein in the uterus. The present results show that the production of the cell cycle factors, cyclin B1, cdc2 p34 and c-fos, during rat uterine growth are under different regulatory controls. cdc2 p34 and c-fos 28 kDa protein are under the control of estradiol; whereas cyclin B1 and the majority of the immunoreactive isoforms of c-fos are not influenced by this hormone.
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PMID:Differential effect of estrogen on the production of cyclin B1, cdc2 p34 and c-fos protein in rat uterus. 788 99


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