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)

Growth factor-induced signals govern the expression of three D-type cyclins, which, in turn, function as regulatory subunits of cyclin-dependent kinases (cdks) to control cell cycle transitions during the late G1 interval. 32D myeloid cells, which self-renew as uncommitted precursors in interleukin 3 (IL-3), express cyclins D2 and D3 (but not D1) in complexes with cdk4 and cdk2. When transferred to granulocyte colony-stimulating factor (G-CSF), 32D cells stop dividing and terminally differentiate to mature neutrophils. Cyclin D and cdk4 expression ceased as cells underwent growth arrest in G-CSF, but cdk2 levels were sustained. 32D cells engineered to ectopically express D-type cyclins exhibited contracted G1 intervals with a compensatory lengthening of S phase but remained IL-3 dependent for cell growth; those overexpressing cyclins D2 and D3 (but not D1) were unable to differentiate and died in G-CSF. Cyclin D2 mutants, which cannot efficiently bind to, or functionally interact with, the retinoblastoma protein (pRb) or its relatives (p107) did not block differentiation. Conversely, the introduction of a catalytically inactive cdk4 mutant into cells overexpressing cyclin D2 restored their G-CSF response. The persistence of cdk2 and its predilection to functionally interact with cyclins D2 and D3 rather than D1 might explain the specificity of the differentiation blockade.
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PMID:Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1. 750 40

The mitogen-dependent induction of cyclin D-dependent kinase activity is required for cells to enter the DNA synthetic (S) phase of their division cycle. Immature 32Dcl3 myeloid cells (32D) proliferating in the presence of interleukin-3 (IL-3) normally express cyclins D2 and D3, which assemble into binary holoenzyme complexes with their catalytic subunits, CDK4 and CDK6. When 32D cells are switched to medium containing granulocyte colony-stimulating factor (G-CSF) instead of IL-3, D-type cyclins are degraded and, in the absence of their associated kinase activity, the cells arrest in the first gap phase (G1) of the cell cycle and differentiate to neutrophils. We derived 32D cells in which the expression of p19INK4d, a specific polypeptide inhibitor of CDK4 and CDK6, is regulated by the heavy metal-inducible sheep metallothionein promoter. Induction of p19INK4d in response to zinc prolonged cell survival in the absence of growth factor treatment. When maintained in medium containing both IL-3 and zinc, these cells lost cyclin D-dependent kinase activity, underwent G1 phase arrest, and acquired certain morphologic, antigenic, and functional properties of mononuclear phagocytes. Cells induced to express p19INK4d did not synthesize receptors for macrophage colony-stimulating factor (M-CSF/CSF-1) and reverted to an immature myeloid phenotype when shifted back into medium containing IL-3 alone. These cells exhibited accelerated differentiation to neutrophils in response to G-CSF but also gave rise to macrophage-like cells when maintained in medium containing both G-CSF and zinc. Therefore, the acquisition of macrophage properties in response to zinc treatment neither depended upon IL-3 nor upon G1 phase arrest per se and instead reflects some ability of p19INK4d, and presumably cyclin D-dependent kinases, to affect myeloid differentiation.
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PMID:Features of macrophage differentiation induced by p19INK4d, a specific inhibitor of cyclin D-dependent kinases. 920 46

We previously reported that injection of recombinant granulocyte colony-stimulating factor (G-CSF) suppressed the development of leukemia in mice transplanted with C2M-A5 (C2M) myeloid leukemia cells and that the anti-leukemic effect of G-CSF was ascribed to the induction of apoptosis of C2M cells. These observations make a striking contrast with other previous reports on the biological activities of G-CSF. In the present study, in order to further clarify the G-CSF-induced apoptosis of C2M cells, we studied the effects of G-CSF on the cell cycle as well as the molecular events involving D-type cyclines and their cyclin-dependent kinases (cdk) in G-CSF-treated C2M cells. Cell cycle analysis revealed that G-CSF treatment of C2M cells resulted in accelerated entry from the first gap (G1) phase into the DNA synthesis (S) phase. Western blotting disclosed that G-CSF treatment resulted in down-regulation of cyclin D2 and cdk2 and up-regulation of cyclin D1 and cdk4. The reciprocal relationship between the up-regulation of cyclin D1 and down-regulation of cyclin D2 was closely associated with accelerated entry into S phase and subsequent apoptosis of C2M cells. These results suggest that G-CSF-induced apoptosis of C2M cells might be ascribed to imbalanced cell cycle progression due to deregulated expression of D-type cyclins and their cdks.
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PMID:Accelerated entry into S phase associated with up-regulation of cyclin D1 as a mechanism for granulocyte colony-stimulating factor (G-CSF)-induced apoptosis of murine myeloid leukemia cells. 961 17

Jak3, a member of the Janus kinase family of cytoplasmic tyrosine kinases, is expressed at low levels in immature hematopoietic cells and its expression is dramatically up-regulated during the terminal differentiation of these cells. To better understand the role of Jak3 in myeloid cell development, we have investigated the role of Jak3 in myeloid cell differentiation using the 32Dcl3 cell system. Our studies show that Jak3 is a primary response gene for granulocyte colony-stimulating factor (G-CSF) and the accumulation of tyrosine phosphorylated Jak3 correlated with cell growth inhibition and terminal granulocytic differentiation in response to G-CSF. Ectopic overexpression of Jak3 in 32Dcl3 cells resulted in an acceleration of the G-CSF-induced differentiation program that was preceded by G(1) cell cycle arrest, which was associated with the up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) and down-regulation of Cdk2, Cdk4, Cdk6, and Cyclin E. In addition, ectopic overexpression of Jak3 appears to result in the inactivation of PKB/Akt and Stat3-mediated proliferative pathways in the presence of G-CSF. Similarly, overexpression of Jak3 in primary bone marrow cells resulted in an acceleration of granulocytic differentiation in the presence of granulocyte-macrophage colony-stimulating factor, which was associated with their growth arrest in the G(1) phase of the cell cycle. Taken together, these results indicate that Jak3-mediated signals play an important role in myeloid cell differentiation.
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PMID:Activation of the Jak3 pathway is associated with granulocytic differentiation of myeloid precursor cells. 1235 82

We have investigated the role of tyrosine phosphorylation of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 using the acute promyelocytic leukemia cell line NB4 together with granulocyte colony-stimulating factor (G-CSF). Short-term G-CSF stimulation resulted in a rapid tyrosine dephosphorylation of p27Kip1 accompanied by a change in its binding preferences to cdks. On G-CSF stimulation, p27Kip1 dissociated from cdk4 and associated with cdk2. Binding assays with recombinant p27Kip1 confirmed that tyrosine-phosphorylated p27Kip1 preferentially bound to cdk4, whereas unphosphorylated protein preferentially associated with cdk2. In addition, studies with p27Kip1 point mutations revealed a decisive role of Tyr88 and Tyr89 in binding to cdk4. Furthermore, phosphorylation of Tyr88 and Tyr89 was accompanied by strong nuclear translocation of p27Kip1. Taken together, this report provides the first evidence that tyrosine phosphorylation of p27Kip1 plays a crucial role in binding to cdks and its subcellular localization. Moreover, both effects are mediated by application of G-CSF.
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PMID:Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4. 1619 27