Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 melanoma cell lines derived from early stage primary tumors are particularly sensitive to growth arrest induced by interleukin-6 (IL-6). This response is lost in cell lines derived from advanced lesions, a phenomenon which may contribute to tumor aggressiveness. We sought to determine whether resistance to growth inhibition by IL-6 can be explained by oncogenic alterations in cell cycle regulators or relevant components of intracellular signaling. Our results show that IL-6 treatment of early stage melanoma cell lines caused G1 arrest, which could not be explained by changes in levels of G1 cyclins (D1, E), cdks (cdk4, cdk2) or by loss of cyclin/cdk complex formation. Instead, IL-6 caused a marked induction of the cdk inhibitor p21WAF1/CIP1 in three different IL-6 sensitive cell lines, two of which also showed a marked accumulation of the cdk inhibitor p27Kip1. In contrast, IL-6 failed to induce p21WAF1/CIP1 transcript and did not increase p21WAF1/CIP1 or p27kip1 proteins in any of the resistant lines. In fact, of five IL-6 resistant cell lines, only two expressed detectable levels of p21WAF1/CIP1 mRNA and protein, while in three other lines, p21WAF1/CIP1 was undetectable. IL-6 dependent upregulation of p21WAF1/CIP1 was associated with binding of both STAT3 and STAT1 to the p21WAF1/CIP1 promoter. Surprisingly, however, IL-6 stimulated STAT binding to this promoter in both sensitive and resistant cell lines (with one exception), suggesting that gross deregulation of this event is not the unifying cause of the defect in p21WAF1/CIP1 induction in IL-6 resistant cells. In somatic cell hybrids of IL-6 sensitive and resistant cell lines, the resistant phenotype was dominant and IL-6 failed to induce p21WAF1/CIP1. Thus, our results suggest that in early stage human melanoma cells, IL-6 induced growth inhibition involves induction of p21WAF1/CIP1 which is lost in the course of tumor progression presumably as a result of a dominant oncogenic event.
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PMID:Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. 1002 78

Cytokines exert pleiotropic effects on target cells in a manner dependent on the cell type or stage of differentiation. To determine how instinctive cell properties affect biological effects of cytokine, we introduced an erythroid/megakaryocyte lineage-specific transcription factor, GATA-1, into a murine myeloid cell line M1, which is known to undergo macrophage differentiation in response to interleukin 6 (IL-6). Overexpression of GATA-1 changed the phenotype of M1 cells from myeloid to megakaryocytic lineage. Furthermore, GATA-1 blocked both IL-6-induced macrophage differentiation and apoptosis of M1 cells. Although STAT3 is essential for IL-6-induced macrophage differentiation of M1 cells, GATA-1 had little or no effect on tyrosine phosphorylation, DNA binding, and transcriptional activities of STAT3 in Western blot analysis, electropholic mobility shift assay (EMSA), and luciferase assays. During IL-6-induced macrophage differentiation of M1 cells, IL-6 down-regulated cyclin D1 expression and induced p19(INK4D) expression, leading to reduction in cdk4 activities. In contrast, sustained expression of cyclin D1 and a significantly lesser amount of p19(INK4D) induction were observed in IL-6-treated M1 cells overexpressing GATA-1. Furthermore, although bcl-2 expression was severely reduced by IL-6 in M1 cells, it was sustained in GATA-1-introduced M1 cells during the culture with IL-6. Both IL-6-induced macrophage differentiation and apoptosis were significantly abrogated by coexpression of cyclin D1 and bcl-2, whereas overexpressions of cyclin D1 or bcl-2 inhibited only differentiation or apoptosis, respectively. These results suggested that GATA-1 may not only reprogram the lineage phenotype of M1 cells but also disrupt the biologic effects of IL-6 through the sustained expression of cyclin D1 and bcl-2. (Blood. 2000;95:1264-1273)
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PMID:GATA-1 blocks IL-6-induced macrophage differentiation and apoptosis through the sustained expression of cyclin D1 and bcl-2 in a murine myeloid cell line M1. 1066 99

While the activated viral Src oncoprotein, v-Src, induces uncontrolled cell growth, the mechanisms underlying cell cycle deregulation by v-Src have not been fully defined. Previous studies demonstrated that v-Src induces constitutively active STAT3 signaling that is required for cell transformation and recent data have implicated STAT3 in the transcriptional control of critical cell cycle regulators. Here we show in mouse fibroblasts stably transformed by v-Src that mRNA and protein levels of p21 (WAF1/CIP1), cyclin D1, and cyclin E are elevated. Using reporter constructs in transient-transfection assays, the cyclin D1 and p21 promoters were both found to be transcriptionaly induced by v-Src in a STAT3-dependent manner. The kinase activities of cyclin D/CDK4, 6 and cyclin E/CDK2 complexes were only slightly elevated, consistent with the findings that coordinate increases in p21, cyclin D1 and cyclin E resulted in an increase in cyclin/CDK/p21 complexes. Similar results were obtained in NIH3T3 and BALB/c 3T3 cells stably transformed by v-Src, indicating that these regulatory events associated with STAT3 signaling represent common mechanisms independent of cell line or clonal variation. These findings suggest that STAT3 has an essential role in the regulation of critical cell cycle components in v-Src transformed mouse fibroblasts.
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PMID:Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling. 1111 18

Pancreatic ductal adenocarcinoma (PDAC) cell lines, MIA PaCa-2, and UK Pan-1, were used to investigate the role of ErbB2 in PDAC oncogenesis. Both these cell lines exhibit exogenous growth factor-independent proliferation that was attributed to the production of autocrine growth factors and/or overexpression of growth factor receptors. The exogenous growth factor-independent phenotype displayed by these PDAC cell lines was dependent on ErbB2 kinase activity since treatment of cells with tyrphostin AG879 prevented serum-free media (SFM) induction of cell proliferation. We determined that ErbB2 kinase contributed to aberrant cell cycle regulation in PDAC through the induction of cyclin D1 levels and the suppression of p21(Cip1) and p27(Kip1). Inhibition of ErbB2 kinase led to cell cycle arrest marked by an increased association of p27(Kip1) with cdk2 and reduced levels of phosphorylated pRb. We further observed constitutive STAT3 activation in the PDAC cell lines and an increase in STAT3 activation upon stimulating quiescent cells with SFM. Inhibitors of ErbB2 kinase blocked STAT3 activation, whereas inhibition of EGFR kinase led to a slight reduction of STAT3 activation. STAT3 was coimmunoprecipitated with ErbB2. SFM stimulation caused an increase in the association of ErbB2 and STAT3, which was blocked by inhibition of ErbB2 kinase. Expression of a STAT3 dominant negative prevented SFM-stimulated cell proliferation of MIA PaCa-2 cells, suggesting that activation of STAT3 by ErbB2 is required for a growth factor-independent phenotype of these cells. Consistent with this observation in PDAC cell lines, we found that most PDAC tumor specimens (10 of 11) showed constitutive activation of STAT3 and that ErbB2 was readily detected in most of these tumors (nine of 11). We believe that these findings indicate a novel mechanism of oncogenesis in PDAC and may suggest future therapeutic strategies in the treatment of PDAC.
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PMID:Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. 1458 4

Hepatocyte proliferation represents an important part of tissue repair. In these studies, TNF receptor 1 (TNFR1) knockout mice were used to analyze the role of TNF-alpha in hepatocyte proliferation during acetaminophen-induced hepatotoxicity. Treatment of wild-type (WT) mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis. This was associated with proliferation of hepatocytes surrounding the damaged areas, which was evident at 24 h. The cell cycle regulatory proteins, cyclin D1 and cyclin A, were also up regulated in hepatocytes. In contrast, in TNFR1-/- mice, which exhibit exaggerated acetaminophen hepatotoxicity, hepatocyte proliferation, and expression of cyclin D1 and cyclin A, as well as the cyclin dependent kinases, Cdk4 and Cdk2, were reduced. The cyclin-dependent kinase inhibitor p21 was also induced in the liver following acetaminophen administration. This was greater in TNFR1-/- mice compared to WT mice. To investigate mechanisms mediating the reduced hepatic proliferative response of TNFR1-/- mice, we analyzed phosphatidyl inositol-3-kinase (PI-3K) signaling. In both WT and TNFR1-/- mice, acetaminophen caused a rapid increase in total PI-3K within 3 h. Acetaminophen also increased phosphorylated PI-3K, but this was delayed 6-12 h in TNFR1-/- mice. Expression of Akt, a downstream target of PI-3K, was increased in both WT and TNFR1-/- mice in response to acetaminophen. However, the increase was greater in WT mice. Acetaminophen-induced expression of phosphorylated STAT3, a key regulator of cytokine-induced hepatocyte proliferation, was also delayed in TNFR1-/- mice relative to WT. These data suggest that TNF-alpha signaling through TNFR1 is important in regulating hepatocyte proliferation following acetaminophen-induced tissue injury. Delayed cytokine signaling may account for reduced hepatocyte proliferation and contribute to exaggerated acetaminophen-induced hepatotoxicity in TNFR1-/- mice.
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PMID:Role of tumor necrosis factor receptor 1 (p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice. 1464 24

STAT transcription factors (signal transducers and activators of transcription) are cytoplasmic proteins that induce gene activation in response to cytokine receptor stimulation. Following tyrosine phosphorylation, STAT proteins translocate into the nucleus and activate specific target genes. We have previously reported that STAT3 activates the expression of the p21waf1 gene through its association with the NcoA/SRC1a and CBP coactivators. In this study, we explore the role of BRG1, a component of the SWI/SNF chromatin-remodeling complex, and the role of cdk9, a component of the elongation factor P-TEFb, in the STAT3-mediated expression of p21waf1. We found using pull-down experiments and co-immunoprecipitation assays that both proteins associate with STAT3. Chromatin immunoprecipitation (ChIP) experiments indicate that STAT3 DNA binding results in histone H3 acetylation and BRG1 recruitment. Using Southern blot analysis, we found that the loading of BRG1 is followed by an increased accessibility of the proximal p21waf1 promoter and by the association of RNA polymerase II. As a next step, STAT3 then recruits the cdk9 kinase to phosphorylate the carboxy-terminal domain of the RNA polymerase at serine 2. Accordingly, the elongating form of the polymerase can be detected by ChIP experiments on the coding region of the gene, probably initiating mRNA synthesis. Therefore, STAT3 not only promotes the initiation of transcription but also regulates chromatin remodeling and transcription elongation through its interaction with BRG1 and cdk9.
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PMID:Implication of BRG1 and cdk9 in the STAT3-mediated activation of the p21waf1 gene. 1528 5

Pyrrolizidine alkaloids initiate disease in the lung (pulmonary hypertension), liver (veno-occlusive disease and cirrhosis), and kidneys (afferent arteriolar block and mesangiolysis) by inducing a megalocytotic phenotype in target endothelial and parenchymal cells. A "hit-and-run" type of exposure to the bioactive pyrrolizidine results, within 2-3 days, in enlarged cells with large nuclei and enlarged Golgi and endoplasmic reticulum, while the cells remain in G2/M block. In the present study, we recapitulated monocrotaline pyrrole (MCTP)-induced megalocytosis in cultures of bovine pulmonary arterial endothelial cells (PAEC), human Hep3B hepatocytes, human type II-like alveolar epithelial cells (A549), and human pulmonary arterial smooth muscle cells (PASMC) and investigated the subcellular mechanism involved. There was an inverse relationship between reduction in caveolin (Cav)-1 levels and stimulation of promitogenic STAT3 and ERK1/2 cell signaling. In megalocytotic PAEC, the Golgi scaffolding protein GM130 was shifted from membranes with heavy density to those with a lighter density. This lighter Golgi fraction was enriched for hypo-oligomeric Cav-1, indicating dysfunctional trafficking of cargo. Immunofluorescence imaging studies confirmed the trapping of Cav-1 in a GM130-positive Golgi compartment. There was an increase in Ser25 phosphorylation of GM130 (typically a prelude to Golgi fragmentation and mitosis) and increased association between pGM130, cdc2 kinase, and Cav-1. Nevertheless, megalocytotic MCTP-treated cells showed reduced entry into mitosis upon stimulation with 2-methoxyestradiol (2-ME), reduced 2-ME-induced Golgi fragmentation, and a slowing of Golgi reassembly after nocodazole-induced fragmentation. These data suggest that a disruption of the trafficking and mitosis sensor functions of the Golgi may represent the subcellular mechanism leading to MCTP-induced megalocytosis ("the Golgi blockade hypothesis").
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PMID:Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism. 1556 61

Although the role of Jak3 in lymphoid development has been well-characterized, increasing evidence demonstrates that activation of the Jak3 pathway plays an important role in myeloid differentiation as well. Overexpression of Jak3 in murine myeloid 32Dcl3 cells has been shown to result in an acceleration of granulocytic differentiation induced by G-CSF. Early onset of G1 cell cycle arrest along with upregulation of the cyclin dependent kinase inhibitor p27Kip1 and downregulation of Cdk2, Cdk4, Cdk6, and Cyclin E has also been observed in Jak3-overexpressing 32Dcl3 cells. In addition, Jak3 overexpression in normal mouse bone marrow cells results in accelerated granulocytic and monocytic differentiation in response to GM-CSF, while pharmacological inhibition of Jak3 results in a block to GM-CSF-induced colony formation in normal mouse bone marrow cells. Jak3 is unique among the members of the Jak kinase family in that it is inducibly expressed and is a target for regulation at the level of transcription. Recent studies have demonstrated that upregulation of Jak3 during myeloid differentiation is achieved through the cooperative action of Sp1 and STAT3, consistent with evidence indicative of a crucial role for STAT3 in myeloid differentiation. These results suggest that cytokine-inducible activation of Jak3 plays a critical role in integrating the processes of growth arrest and differentiation of myeloid cells.
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PMID:Activation of the Jak3 pathway and myeloid differentiation. 1562 77

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.
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PMID:Kinases as drug discovery targets in hematologic malignancies. 1630 89

Monocrotaline (MCT) causes pulmonary hypertension in the rat by a mechanism characterized by megalocytosis (enlarged cells with enlarged endoplasmic reticulum and Golgi and a cell cycle arrest) of pulmonary arterial endothelial (PAEC), arterial smooth muscle, and type II alveolar epithelial cells. In cell culture, although megalocytosis is associated with a block in entry into mitosis in both lung endothelial and epithelial cells, DNA synthesis is stimulated in endothelial but inhibited in epithelial cells. The molecular mechanism(s) for this dichotomy are unclear. While MCTP-treated PAEC and lung epithelial (A549) cells both showed an increase in the "promitogenic" transcription factor STAT3 levels and in the IL-6-induced nuclear pool of PY-STAT3, this was transcriptionally inactive in A549 but not in PAEC cells. This lack of transcriptional activity of STAT3 in A549 cells correlated with the cytoplasmic sequestration of the STAT3 coactivators CBP/p300 and SRC1/NcoA in A549 cells but not in PAEC. Both cell types displayed a Golgi trafficking block, loss of caveolin-1 rafts, and increased nuclear Ire1alpha, but an incomplete unfolded protein response (UPR) with little change in levels of UPR-induced chaperones including GRP78/BiP. There were discordant alterations in cell cycle regulatory proteins in the two cell types such as increase in levels of both cyclin D1 and p21 simultaneously, but with a decrease in cdc2/cdk1, a kinase required for entry into mitosis. While both cell types showed increased cytoplasmic geminin, the DNA synthesis-initiating protein Cdt1 was predominantly nuclear in PAEC but remained cytoplasmic in A549 cells, consistent with the stimulation of DNA synthesis in the former but an inhibition in the latter cell type. Thus differences in cell type-specific alterations in subcellular trafficking of critical regulatory molecules (such as CBP/p300, SRC1/NcoA, Cdt1) likely account for the dichotomy of the effects of MCTP on DNA synthesis in endothelial and epithelial cells.
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PMID:Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells. 1641 77


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