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 have analysed the expression of 7 cyclin and cyclin-associated kinase (cdk) genes in the human myeloid cell line HL-60 at different stages of the cell cycle in non-synchronised cells and during terminal differentiation. A clear cell cycle-dependent expression was found with cyclins A (S+G2), B (G2) and E (late G1 and S), while other cell cycle genes showed only very weak (cdk2) or no periodic expression (cyclin D1, cyclin D2 and cdk4). Induction of macrophage-like differentiation by TPA or granulocytic differentiation by retinoic acid or DMSO was accompanied by a block in G1 and resulted in distinct patterns of gene expression that were lineage- and inducer-specific. These included: (i) a dramatic decrease in the expression of cyclin A, cyclin B and cdk2, and surprisingly an up-regulation of cyclin D1 in TPA-induced macrophage-like cells; (ii) a down-regulation of cyclin E in retinoic acid-induced granulocytic cells; and (iii) a decreased abundance of cyclin D1 and D2, but high levels of cyclin A, B and E RNA in DMSO-induced granulocytic cells. These observations suggest that the mechanisms leading to a differentiation-associated cell cycle arrest are lineage-specific, and that the sustained expression of cyclin and cdk genes does not interfere with the induction of terminal differentiation.
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PMID:Lineage-specific regulation of cell cycle gene expression in differentiating myeloid cells. 798 66

Differentiation induction by 12-o-tetradecanoyl 13-acetate (TPA) results in the growth arrest of HL60 cells in the G1 phase. However, little is known about the changes of cell cycle-regulating genes during this differentiation process. We investigated the changes of mRNA for various cyclins (A, C, D1, D2, D3 and E) and cdk2. Synchronized HL60 cells began to proliferate immediately after release from cell cycle block and cell cycle synchrony was obvious until the second S phase. TPA-treated cells accumulated in G1 phase within 24 h and most of the cells were arrested in this phase at 36 h. The expression of cyclins and cdk2 was studied by Northern blot hybridization of the reverse-transcription polymerase chain reaction (RT-PCR). TPA treatment altered the expression of all genes studied. The expression of cdk2 and cyclin A mRNA was markedly down-regulated. Cyclin E mRNA expression was also prominently down-regulated from 12 h to 36 h, at which time a second increase of its expression was observed in control cells. In contrast, the expression of cyclin D1 mRNA was induced by TPA, while its expression in control cells was undetectable by Northern blot hybridization throughout the cell cycle. Cyclin C expression was faint and fluctuated irrelevant of cell cycle, but its expression in both control and TPA-treated cells was higher than at baseline. Cyclin D2 expression remained stable in control cells and TPA treatment resulted in slight down-regulation at 12 h, but no difference was observed after 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes of G1 cyclins, cdk2, and cyclin A during the differentiation of HL60 cells induced by TPA. 807 6

Differentiation leads to the cessation of cellular proliferation, but little is known about the molecular mechanisms of growth arrest. We compared the effect of two differentiation inducers, 12-o-tetradecanoyl 13-acetate (TPA) and dimethyl sulfoxide (DMSO) on both the cell-cycle and the modulation of G2-related genes in synchronized HL60 cells. TPA treatment of HL60 cells resulted in G1 arrest within 24 h. In contrast, the cell cycling of DMSO-treated cells was initially accelerated and they progressed to the second cycle before accumulating in the G1 phase. Expression of cyclin B, cdc25, wee1 and cdc2 was studied during cell cycle arrest by Northern blot hybridization. Expression of cyclin B, cdc25 and cdc2 fluctuated in association with cell cycle progression towards the G2/M phase, while wee1 expression remained constant in untreated cells. These four genes were highly expressed in TPA-treated cells for the first 12 h, but drastic down-regulation was seen at 18 h and expression became undetectable after 24 h. In contrast, no remarked changes of gene expression were seen in DMSO-treated cells. These findings suggest that cell cycle progression along with the initial process of differentiation in response to TPA differs from the response to DMSO and that the down-regulation of cdc2 expression by TPA-treated HL60 cells contributes to endorsement of G1 arrest.
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PMID:Differing responses of G2-related genes during differentiation of HL60 cells induced by TPA or DMSO. 845 82

Tissue polypeptide antigen has been advocated over the past two decades as a serum tumour marker. It was a long time before it was proven that these proteins in the serum are related to cytokeratin fragments. In this study the different behaviour of the test systems TPA, TPS, TPA(cyk) and CYFRA 21.1 were investigated in serum samples, mainly of metastasized cancer patients. By selecting individual samples with a high and a low TPA/TPS ratio it could be proven that no correlation existed in these samples between TPS (determining fragments of cytokeratin 18) and CYFRA 21.1 (determining fragments of cytokeratin 19). On the contrary, a good correlation was established between the TPA test and the CYFRA 21.1 test, and intermediate correlations were present between these tests and TPA (cyk). The TPA (cyk) test determines cytokeratin 8 and 18 fragments. During therapy, monitoring of metastasized patients with these tests could show a different pattern of reactivity. It is concluded that the different test results during therapy monitoring are not always easy to interpretate. The release of cytokeratins from cancer cells needs further study.
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PMID:Significance of cytokeratin markers TPA, TPA (cyk), TPS and CYFRA 21.1 in metastatic disease. 869 67

In most eukaryotic cells, a link between S and M phases of the cell cycle must be assured in order to maintain the ploidy of newly divided cells. However, in some cell l/pes, e.g. the precursors of platelets megakaryocytes, extra S-phases can occur in the absence of concomitant mitoses, resulting in polyploidy. We have used two established cell lines with megakaryoblastic characteristics (HEL and MEG-01) to investigate the molecular events that lead these cells to bypass the regular control checkpoints that govern the interdependency of S and M phases. In the presence of the phorbol ester TPA, both cell lines stopped proliferating and displayed additional megakaryocytic features, including polyploidization. Analysis of key cell cycle regulatory factors implicated in the control of G1/S and G2/M transitions revealed a number of differences compared to normally cycling cells. Differentiating megakaryocytes were found to maintain high levels of cdk2, and cyclins E and A. This was accompanied by the appearance of the retinoblastoma protein in the hyperphosphorylated, functionally inactivated form. In addition, TPA-treated cells showed high levels of cyclin B and cdc2 proteins, however no activation of cdc2 was detected. This lack of cdc2 activation which should occur for entry into M phase appeared to be related to the down regulation of cdc25C phosphatase found in both differentiated HEL and MEG-01 cells. Together, our results suggest that in differentiating megakaryoblastic cells endoreplication is accompanied by sustained levels of cyclins A and E, and a lack of cdc2 activation, which is probably mediated through down regulation of cdc25C protein phosphatase.
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PMID:Endoreplication in megakaryoblastic cell lines is accompanied by sustained expression of G1/S cyclins and downregulation of cdc25C. 876 Dec 90

Endomitosis (polyploidization) is a distinctive feature of megakaryocyte differentiation. We examined this mechanism in an erythromegakaryocytic cell line, HEL, using a protein kinase inhibitor K252a or a phorbol-ester TPA. HEL cells treated with K252a showed a marked increase in the proportion of CD41 positive cells and polyploid cells as well as in cellular size and nuclear size. TPA showed similar results but induced multi-nucleation instead of enlargement of nuclear size. K252a added at the G1/S boundary phase did not inhibit the first and second round DNA synthesis, but inhibited cell division. K252a did not inhibit the expression of genes involved in mitosis such as cyclin B, cdc25B and cdc2, in the first round S phase. However, the cyclin B associated Cdc2 kinase activity needed for mitosis during the G2/M phase was reduced by K252a. TPA delayed DNA synthesis and expression of these genes, and suppressed Cdc2 kinase activity in the second round G2/M phase. These results suggest that the polyploidization induced by K252a results from inhibiting mitosis possibly caused by suppression of Cdc2 kinase activity. TPA may induce the multi-nucleation through a different mechanism.
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PMID:Induction of polyploidization in the human erythroleukemia cell line (HEL) by protein kinase inhibitor (K252a) and the phorbol-ester TPA. 916 44

The v-Myb DNA-binding domain differs from that of c-Myb mainly by deletion of the first of three repeats. This truncation correlates with efficient oncogenic transformation and a decrease in DNA-binding activity. Here we demonstrate that the D-type cyclins, cyclin D1 and D2 in particular, specifically inhibit transcription when activated through the v-Myb DNA-binding domain, but not the c-Myb DNA-binding domain. Analysis of a cyclin D1 mutant and a dominant-negative CDK4 mutant implied that this repression is independent of complex formation with a CDK partner. Association of cyclin D1 and D2 with the Myb DNA-binding domain could be demonstrated. Increased levels of cyclin D1 and D2 resulted in a stabilization of the Myb proteins, but not in an alteration in binding of the Myb proteins to DNA. These results highlight an unexpected role for cyclin D as a CDK-independent repressor of transcriptional activation by v-Myb but not c-Myb. This differential effect of D-type cyclins on v-Myb and c-Myb might help to explain the mechanism underlying the oncogenic activity of v-Myb, which appears to be a stronger transcriptional activator following the TPA-induced differentiation of transformed monoblasts when cyclin D1 and D2 are down-regulated.
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PMID:D-type cyclins repress transcriptional activation by the v-Myb but not the c-Myb DNA-binding domain. 942 59

Protein kinase C (PKC) is reversibly activated at the plasma membrane by the generation of diacylglycerol (DAG) coupled with the release of Ca2+ from intracellular stores. PKC is also irreversibly activated by calpain-mediated PKC cleavage of the regulatory and catalytic subunits; resultant free PKC catalytic subunits are termed "PKM". Unlike PKC, PKM is co-factor-independent, remains active following diffusion away from the membrane, and can theoretically phosphorylate targets inaccessible to, and inappropriate for, PKC. We examined the downstream consequences of PKC activation by the phorbol ester TPA and by ionophore A23187-mediated calcium influx (which experimentally correspond to DAG-mediated and calpain-mediated activation, respectively) on phosphorylation of the microtubule-associated protein tau. Both methods increased phospho-tau immunoreactivity, and neither was inhibited by lithium or olomoucin (inhibitors of tau kinases GSK-3 beta and cdk5, respectively). The TPA-mediated increase, and not the ionophore-mediated increase, was blocked by co-treatment with the mitogen-activated protein (MAP) kinase kinase inhibitor PD98059. These findings indicate that PKC phosphorylates tau via the MAP kinase pathway, but that PKM can bypass this requirement, therefore demonstrating that distinct intracellular pathways can be mediated by PKC and PKM. PKM generation may therefore trigger one or more additional pathways contributing to tau phosphorylation following inappropriate calcium influx.
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PMID:Free PKC catalytic subunits (PKM) phosphorylate tau via a pathway distinct from that utilized by intact PKC. 1062 66

Saikosaponin a, a purified ingredient of Chinese herb with known antitumor activity, can inhibit cell growth and DNA synthesis of hepatoma cell line HepG2. Both mRNA and protein of the CDK inhibitor p-16(INK4a) and p-15(INK4b) in HepG2 were greatly induced by saikosaponin a while that of p-21(CIP), p-27(KIP) and other cell cycle related genes were not. In addition, reduced phosphorylation of RB protein is observed in saikosaponin a-treated HepG2. Staurosporin, one of the PKC inhibitors, significantly prevented the saikosaponin a induced growth inhibition suggesting PKC pathway be involved. On the other hand, the phorbol ester tumor promoter TPA (12-O-Tetredecanolyphorbol 13-acetate) also inhibited HepG2 growth and specifically induced p-16(INK4a) and p-15(INK4b) mRNA expression. The results suggest that both saikosaponin a and TPA-induced HepG2 growth inhibition are associated with p-15(INK4a) and p-16(INK4b) gene expression and might be mediated by PKC signaling pathway.
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PMID:Involvement of p-15(INK4b) and p-16(INK4a) gene expression in saikosaponin a and TPA-induced growth inhibition of HepG2 cells. 1144 23

Expression of cell cycle-regulating genes was studied in human myeloid leukemia cell lines ML-1, ML-2 and ML-3 during induction of differentiation in vitro. Myelomonocytic differentiation was induced by phorbol ester (12-o-Tetradecanoyl-phorbol-13-acetate, TPA), tumor necrosis factor alpha (TNFalpha) or interferon gamma (INFgamma), or their combination. Differentiation (with the exception of TNFalpha alone) was accompanied by inhibition of DNA synthesis and cell cycle arrest. Inhibition of proliferation was associated with a decrease in the expression of cdc25A and cdc25B, cdk6 and Ki-67 genes, and with increased p21(Waf1/Cip1) gene expression, as measured by comparative RT-PCR. Expression of the following genes was not changed after induction of differentiation: cyclin A1, cyclin D3, cyclin E1 and p27(Kip1). Surprisingly, cyclin D1 expression was upregulated after induction by TPA, TNFalpha with IFNgamma or BA. Cyclin D2 was upregulated only after induction by BA. The results of the expression of the tested genes obtained by comparative RT-PCR were confirmed by quantitative real-time (RQ) RT-PCR and Western blotting. Quantitative RT-PCR showed as much as a 288-fold increase of cyclin D1 specific mRNA after a 24h induction by TPA. The upregulation of cyclin D1 in differentiating cells seems to be compensated by the upregulation of p21(Waf1/Cip1). These results, besides others, point to a strong correlation between the expression of cyclin D1 and p21(Waf1/Cip1) on the one hand and differentiation on the other hand in human myeloid leukemic cells and reflect a rather complicated network regulating proliferation and differentiation of leukemic cells.
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PMID:Relationship between cyclin D1 and p21(Waf1/Cip1) during differentiation of human myeloid leukemia cell lines. 1292 50


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