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)

The binding of viral oncogenes to cellular proteins is thought to modulate the activities of these cellular targets. The p107 protein is targeted by many viral proteins, including adenovirus E1A, simian virus 40 large T antigen, and human papillomavirus type 16 E7 protein. A panel of monoclonal antibodies against p107 was raised and used to identify cellular proteins that interact with the p107 protein in vivo. p107-associated proteins included cyclin A, cyclin E, and cdk2. In addition, p107 was found to associate with 62- to 65- and 50-kDa phosphoproteins in ML-1 cells, a human myeloid leukemia cell line. The 62- to 65-kDa proteins have many of the properties of the transcription factor E2F but were distinguished from pRB-associated E2F-1 by both immunologic and biochemical properties.
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PMID:Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1. 823 Apr 83

The level of various G1 cyclins and cyclin-dependent kinases (cdks) present in the nuclei of synchronized ML-1 human myeloblastic leukemia cells was determined as a function of time after initiation of cell growth with insulin-like growth factor-1 (IGF-1) and transferrin (Tf), and following induction of differentiation with transforming growth factor-beta1 (TGF-beta1). Cyclin E and cdk2 were expressed at relatively high levels in the nuclei of proliferation-stimulated cells, whereas cyclin D1 and cdk5 were expressed at comparably high levels in the nuclei of differentiation-induced cells. In the nuclear extracts from proliferation-stimulated cells, cyclin E complexed specifically with cdk2, whereas in nuclear extracts from differentiation-induced cells, cyclin D1 bound specifically to cdk5. Increased cyclin E/cdk2 expression was accompanied by increased DNA synthesis, whereas increased cyclin D1/cdk5 levels correlated with decreased DNA synthesis. In both growth- and differentiation-induced cells, cyclin D2 expression preceded the expression of cyclin D3, and a significantly larger amount of these cyclins was present in differentiation- as compared to proliferation-induced cells. In contrast, cdk4 and cdk6 were present at similar levels in the nuclear extracts from both growth- and differentiation-induced cells. These data show that, in ML-1 cells, the proliferation-associated progression from G1 to S, as well as the differentiation-associated transit from G1 to maturation is accompanied by the expression of specific cyclin/cdk pairs, comprising cdk2/cyclin E in growth and cdk5/cyclin D1 in differentiation.
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PMID:Differential expression of proteins regulating cell cycle progression in growth vs. differentiation. 915 Feb 73

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

Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to cytarabine (ara-C) induced an S-phase checkpoint characterized by the inhibition of Cdk2, cell cycle arrest, no change in constitutively active Akt, or low-stress kinase signaling in ML-1 cells. However, inhibition of Chk1 by UCN-01 in S-phase-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK, and a rapid induction of apoptosis. Similarly, primary acute myelogenous leukemia (AML) blasts exposed to ara-C and UCN-01 demonstrated a selective loss in cloning potential when compared with normal progenitors. Therefore, we evaluated a pilot clinical trial of ara-C in combination with UCN-01 in patients with relapsed AML. Blasts from some patients demonstrated a previously activated Chk1-Cdk2 DNA damage response pathway that decreased during therapy. Constitutively phosphorylated Akt kinase declined on addition of UCN-01 to the ara-C infusion, an action accompanied by an activation of JNK and reduction in absolute AML blast counts. Thus, use of UCN-01 in combination with ara-C decreases Chk1 phosphorylation, inhibits the Akt survival pathway, and activates JNK during the course of therapy, offering a rationale for the cytotoxic action of this combination during AML treatment.
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PMID:Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. 1629 3

Phorbol 12-myristate 13-acetate (PMA) is known to affect a variety of cellular processes, including cell proliferation, differentiation, and migration. PMA has been shown to promote antiproliferative and antimigratory effects in many types of cancer cells. Our findings show that PMA induced a strong antiproliferative effect in two anaplastic (FRO and ARO) and one follicular (ML-1) thyroid cancer cell lines, and increased the fraction of FRO cells in G1 phase of the cell cycle. The fractions in the S and G2 phases were decreased. Moreover, PMA evoked a significant increase in the levels of the cell cycle regulators p21Waf1/Cip1 and p27Kip1. The levels of cyclin D3 and the cyclin-dependent kinases cdk4 and cdk6 decreased, as did the phosphorylation of the Rb-protein. PMA did not induce apoptosis. PMA stimulated the translocation of protein kinase C (PKC) alpha, betaI and delta isoforms to the cell membrane. PKCdelta small interfering RNA attenuated the PMA-induced antiproliferative effect and prevented the upregulation of p21Waf1/Cip1 and p27Kip1. Prolonged stimulation with PMA decreased the phosphorylation of mitogen-activated protein (MAP) kinase. PMA also decreased the phosphorylation of Akt and evoked a biphasic change in the phosphorylation of the forkhead box class-O protein (FOXO): an increase in phosphorylation, followed by a dephosphorylation. In addition, PMA inhibited FRO, ARO and ML-1 cell migration toward serum. The inactive phorbol ester analog 4alpha-phorbol and the diacylglycerol analog 1,2-dioctanoyl-sn-glycerol were without an effect on proliferation and migration. The results indicate that PMA is an effective inhibitor of thyroid cancer cell proliferation and migration by a mechanism involving PKC-MAP kinase/Akt and FOXO signaling.
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PMID:Phorbol 12-myristate 13-acetate inhibits FRO anaplastic human thyroid cancer cell proliferation by inducing cell cycle arrest in G1/S phase: evidence for an effect mediated by PKCdelta. 1854 61