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)

The present study examines interferon-gamma (IFN gamma)-induced changes in the expression of immunomodulatory genes, proliferation-associated genes, and squamous-specific genes in primary cultures of human bronchial epithelial cells and fibroblasts. IFN gamma induced the expression of guanylate binding protein (GBP or p67) and the MHC class II antigen, HLADR alpha, in both epithelial cells and fibroblasts. In contrast, the expression of complement component C3 was induced in bronchial epithelial cells but not in fibroblasts. Similarly, IFN gamma induced growth arrest (EC50 approximately 50 U/ml) only in bronchial epithelial cells. This growth arrest was accompanied by a down-regulation of cdc2, E2F-1, and p53 mRNA levels and was associated with expression of the squamous-specific marker genes, transglutaminase type I and cornifin. These findings are consistent with IFN gamma inducing squamous differentiation in bronchial epithelial cells. In contrast, several lung carcinoma cell lines did not respond to IFN gamma with respect to the down-regulation of proliferation-associated genes or the induction of squamous-specific genes. However, GBP expression was induced in all the cell lines in response to IFN gamma. The present study demonstrates that cultured human bronchial epithelial cells are sensitive to the immunomodulatory, growth-inhibitory, and differentiation-inducing properties of IFN gamma. In contrast, several lung carcinoma cell lines are insensitive to the growth-inhibitory and differentiation-inducing actions of IFN gamma, suggesting they may have acquired defects in certain IFN gamma signaling pathways. Although the growth of human bronchial fibroblasts is not altered, expression of certain immunomodulatory genes is induced by IFN gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential responsiveness of human bronchial epithelial cells, lung carcinoma cells, and bronchial fibroblasts to interferon-gamma in vitro. 804 75

Normal human cells from epidermis and from buccal mucosa were cultured to confluence in three media with graded differentiation potential (at low Ca2+, high Ca2+, and supplemented with serum) and treated with transforming growth factor beta 1 (TGF-beta 1), as had been done previously with interferon-gamma (IFN-gamma). The response of the cells to TGF-beta 1 was monitored in terms of the expression of regulatory genes associated with proliferation and differentiation (cdc2, c-myc, p53) and of genes for structural proteins expressed at varying stages of maturation (keratins K5 and K10, involucrin, flaggrin). For both tissues, the results obtained with both agents were very similar for those genes expressed in the basal cells (cdc2, c-myc, p53, K5), regardless of their function, but diverged for the other genes, which are expressed in the suprabasal cells. Another related contrast is that, although IFN-gamma induced apoptosis in epidermal keratinocytes cultured in the serum containing medium, TGF-beta 1 did not. Thus, the two agents appear to affect the earlier stages of cell differentiation in the same way but to differ at the later stages, particularly in that IFN-gamma pushes maturation further than does TGF-beta 1).
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PMID:Response of cultured cells from the epidermis and the buccal mucosa to TGF-beta 1 and comparison to interferon-gamma. 883 86

In this study we examined the regulation of cdk1 expression in normal human epidermal keratinocytes (HEKs) and neoplastic keratinocytes. Keratinocytes were growth-arrested by allowing the cells to grow to confluence or by treating them with interferon-gamma (IFNgamma) or 12-O-tetradecanoyl phorbol-13-acetate (TPA). RT-PCR and Western blot analysis demonstrated that cdk1 was profoundly reduced in growth-arrested HEKs when compared with dividing HEKs. In contrast, a squamous carcinoma cell line, SCC25, did not growth-arrest in response to growth inhibitors and did not downregulate cdk1 expression. Transfection of HEKs with a reporter gene driven off a 2.5-kb fragment of the human cdk1 promoter indicated that the downregulation of cdkl upon growth arrest was transcriptional. Deletion mapping of the cdk1 promoter indicated that a repressor region was located between -949 - -722 bp. This repressor region was not operative in the SCC25 cells. Examination of DNA:protein binding complexes by gel-shift analysis indicated that nuclear factors from both proliferative and growth-arrested cells bound to the DNA fragment spanning -949- -722 bp. Further analysis revealed that this binding could be resolved into a constitutive and growth arrest-specific complex that bound in a similar fashion to regions spanning -892 - -831 bp and -831 - -774 bp, respectively. The putative growth arrest-specific complex was not found in contact-inhibited fibroblasts and was found at very low levels in SCC25 cells, indicating that the putative repressor binding was growth arrest-specific and possibly keratinocyte-specific. The binding complexes bound to these two fragments were localized, by competition analysis, to regions -874 - -853 bp and -830 - -800 bp. This is the first report of a transcriptional repressor being operative during keratinocyte growth arrest.
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PMID:Keratinocyte growth arrest is associated with activation of a transcriptional repressor element in the human cdk1 promoter. 980 55

Cell cycle progression of mouse macrophage cells was impaired by interferon-gamma (IFN-gamma). The blockage of G1/S transition was associated with diminution of cyclin-dependent kinase-2 (CDK2)-associated kinase activities. The expression of p21Cip1 was not upregulated by IFN-gamma. Instead, the physiologic downregulation of p27Kip1 necessary for normal cell cycle progression did not take place sufficiently in the presence of IFN-gamma. During normal cell cycle progression, the levels of p27Kip1 were maximal at early G1 and then decreased gradually. In the presence of IFN-gamma, however, the levels of p27Kip1 discontinued to decrease at a late mid G1 point and were consistently as high as, or higher than, levels observed there. The steady, relatively high-level attachment of p27Kip1 to CDK2 contributed to the insufficient formation of active cyclin/CDK2, possibly deferring cells from entering S phase.
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PMID:Interferon-gamma impairs physiologic downregulation of cyclin-dependent kinase inhibitor, p27Kip1, during G1 phase progression in macrophages. 1002 57

Restenosis after percutaneous transluminal coronary angioplasty (PTCA) and coronary stenting remains a major clinical problem. Vascular smooth muscle cell (SMC) proliferation and migration from the arterial wall media into the intima are believed to play a critical role in the pathogenesis of restenosis. Several studies have demonstrated that phosphorothioate (PS) oligodeoxynucleotides targeted against genes involved in SMC proliferation inhibit in vitro SMC proliferation and migration. Moreover, PS oligodeoxynucleotides targeted against the genes c-myb, c-myc, cdc2 kinase, cdk2 kinase, and proliferating cell nuclear antigen (PCNA) when delivered adventitially or intraluminally inhibit in vivo neointimal formation after balloon injury in both the rat carotid and porcine coronary artery models. The inhibitory effects of these PS oligodeoxynucleotides may be the result of their suppression of migration of medial SMC rather than suppression of medial or intimal cell proliferation. Other studies have demonstrated the presence of the potent guanosine or G-quartet aptameric inhibitory effect of the PS oligodeoxynucleotides. Experiments with cytidine homopolymers such as S-dC28, which lack guanosines, reveal the presence of potent non-G-quartet, non-sequence-specific inhibitory effects on in vitro SMC proliferation, migration, and adhesion as well as in vivo neointimal formation after rat carotid artery balloon injury. This is owing to the avid binding of these PS oligodeoxynucleotides to the SMC mitogens and chemoattractants platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). The extent to which hybridization-dependent antisense, G-quartet aptameric, or non-G-quartet, non-sequence-specific inhibitory effects occurs is the result of PS oligodeoxynucleotide sequence, length, and concentration. The 18-mer guanosine-rich PS oligodeoxynucleotide ZK10 is a more potent in vitro SMC proliferation inhibitor than S-dC28, although both compounds manifest comparable in vivo inhibitory effects on neointimal formation in the rat carotid artery model of balloon injury. PS oligodeoxynucleotides also possess non-sequence-specific immunomodulatory effects, including the induction of interferon-gamma and the unmethylated CpG motif, which exhibits numerous immunomodulatory effects. Novel strategies to inhibit restenosis include the development of E2F transcription decoys that inhibit several cell cycle regulatory genes and diminish neointimal lesion formation. In addition, antisense oligonucleotides targeted against the anti-apoptotic gene bcl-xL, which when transfected into the vessel wall inhibits bcl-xl expression, induce a five-fold increase in apoptotic SMC intimal cells, and effect a marked attenuation of in vivo lesion dimensions, thereby suggesting frank vascular lesion regression.
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PMID:Antisense strategies to inhibit restenosis. 1055 57

Retinoids and interferons have been implicated in the growth regulation of cervical cancer cells. However, the molecular mechanisms are not fully defined. To analyze detailed mechanisms, HPV-positive (HeLa, CaSki), HPV-negative (C33A, HT-3) and non-cervical Cos-1 cell lines were treated with I microM all-trans-retinoic acid (RA) and/or 10 ng/ml interferon-gamma (IFN-gamma). The growth of RA-treated HeLa cells was less effectively suppressed than that of IFN-gamma-treated ones. A combination of RA and IFN-gamma leads to an additive antiproliferative effect on the cell growth. CaSki cell growth was also inhibited by IFN-gamma but was little stimulated by RA treatment, and the IFN effect was attenuated when IFN-gamma was combined with RA. HPV-negative C33A and HT-3 cells, which are defective in p53 and Rb, and Cos- 1 cells were weakly or not responsive to all combined treatments. The molecular mechanism underlying the differential effects of RA/IFN on HeLa and C33A cells was investigated. Combined RA/IFN-gamma treatment caused a marked increase in the level of IFN regulatory factor-1 (IRF-1) in HeLa, whereas no induction of IRF-1 was observed in C33A, consistent with the findings that IFN signaling is functional in HeLa but is defective in C33A cells. The increase of p53 in HeLa cells might account for the down-regulation of HPV-18 E6 gene expression by RA/IFN-gamma. Furthermore, RA/IFN-gamma treatment resulted in the concurrent induction of p21WAF1 CDK inhibitor and dephosphorylation of Rb protein. Transient co-expression of IRF-1 and p53 led to the cooperative activation of the p21WAF1 promoter. Our results indicate that 2 transcription factors, increased in response to RA/IFN-gamma, cooperate functionally to regulate the cell cycle through the activation of a common p21WAF1 gene in HeLa cells.
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PMID:Antiproliferative effects of retinoic acid/interferon in cervical carcinoma cell lines: cooperative growth suppression of IRF-1 and p53. 1065 35

Interferon-gamma induces an irreversible growth arrest and squamous differentiation in normal human epidermal keratinocytes. We present for the first time a careful biochemical analysis of the cell-cycle-related events that occur during interferon-gamma treatment of normal human epidermal keratinocytes. The interferon-gamma-induced irreversible growth arrest state is characterized by inhibition of cyclin-dependent kinases, prevention of Rb and p130 (Rb2) phosphorylation, and increases in p27(Kip1), p16(Ink4a), and p130 proteins, together with a transient increase in p21(Waf1/Cip1). Cells derived from squamous cell carcinomas are less responsive to interferon-gamma and do not terminally differentiate. We exploited these differences in response to interferon-gamma in order to identify the particular molecular defects in cell cycle control that promote carcinogenesis in squamous epithelia. In several squamous cell carcinoma cell lines as well as in interferon-gamma-insensitive HaCaT cells, interferon gamma was unable to significantly induce levels of p130 and/or p16 protein. In addition, p21 association with cdk2 complexes was undetectable in either the absence or the presence of interferon-gamma and, unlike normal human epidermal keratinocytes, p27 association with cdk2 did not increase with interferon-gamma treatment. These multiple defects appear to be intrinsic to the mechanisms of cell cycle regulation rather than due to defects in the interferon-gamma signaling pathway, as induction of several interferon-gamma-responsive genes including Stat 1, IRF-1, and p21 itself was normal. Interestingly, exogenous expression of p21 protein in the squamous cell carcinoma cell lines by adenovirus carrying wildtype p53 or p21 cDNA cooperated with interferon-gamma to produce a greater inhibition of growth than either agent alone, even though p21 protein could barely be detected in cdk2 complexes. We conclude that squamous cell carcinoma cells have intrinsic defects in their ability to regulate cdk-cki complexes in response to differentiation signals.
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PMID:Decreased growth inhibitory responses of squamous carcinoma cells to interferon-gamma involve failure to recruit cki proteins into cdk2 complexes. 1171 Sep 44

Elucidating the factors that inhibit the increase in airway smooth muscle (ASM) mass may be of therapeutic benefit in asthma. Here, we investigated whether interferon-gamma (IFN-gamma), a potent inducer of growth arrest in various cell types, regulates mitogen-induced ASM cell proliferation. IFN-gamma (1-100 U/ml) was found to markedly decrease both DNA synthesis and ASM cell number induced by the mitogens epidermal growth factor (EGF) and thrombin. Interestingly, IFN-gamma had no effect on mitogen-induced activation of three major mitogenic signaling pathways, phosphatidylinositol 3-kinase, p70(S6k), or mitogen-activated protein kinases. Mitogen-induced expression of cell cycle regulator cyclin D1 was increased by IFN-gamma, whereas no effect was observed on degradation of p27(Kip1). Expression array analysis of 23 cell cycle-related genes showed that IFN-gamma inhibited EGF-induced increases in E2F-1 expression, whereas induction of c-myc, cyclin D2, Egr-1, and mdm2 were unaffected. Induction of E2F-1 protein and Rb hyperphosphorylation after mitogen stimulation was also suppressed by IFN-gamma. In addition, IFN-gamma decreased activation of cdk2 and expression of cyclin E, upstream signaling molecules responsible for Rb hyperphosphorylation in the late G1 phase. IFN-gamma also increased levels of IFI 16 protein, whose mouse homolog p202 has been associated with growth inhibition. Together, our data indicate that IFN-gamma is an effective inhibitor of ASM cell proliferation by blocking transition from G1-to-S phase by acting at two different levels: modulation of cdk2/cyclin E activation and inhibition of E2F-1 gene expression.
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PMID:IFN-gamma inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway. 1258 5

To investigate the regulatory effects of decoy receptor 3 (DcR3) on the differentiation and function of dendritic cells (DCs), bone marrow-derived DCs (BM-DCs) from nonobese diabetic (NOD) mice were cultured with recombinant DcR3.Fc protein. Their differentiating phenotypes and T cell-stimulating functions were then evaluated. Expression of CD11c, CD40, CD54, and major histocompatibility complex I-A(g7) was reduced in cells cultured with additional DcR3.Fc, compared with DCs incubated with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4, indicating that DcR3 interferes with the differentiation and maturation of BM-DCs. One of the most striking effects of DcR3.Fc on the differentiation of DCs was the up-regulation of CD86 and down-regulation of CD80, suggesting a modulatory potential to skew the T cell response toward the T helper cell type 2 (Th2) phenotype. Consistent with this, the proliferation of CD4(+) T cells cocultured with DcR3.Fc-treated DCs was significantly reduced compared with that of T cells stimulated by normal DCs. Moreover, the secretion of interferon-gamma from T cells cocultured with DcR3.Fc-treated DCs was profoundly suppressed, indicating that DcR3 exerts a Th1-suppressing effect on differentiating DCs. Furthermore, adoptive transfer experiments revealed that NOD/severe combined immunodeficiency mice received DcR3.Fc-treated DCs, and subsequently, autoreactive T cells showed delayed onset of diabetes and a decrease in diabetic severity compared with mice that received normal DCs and T cells, suggesting a future therapeutic potential in autoimmune diabetes. Data from two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight analysis show an up-regulation of some proteins-such as mitogen-activated protein kinase p38 beta, cyclin-dependent kinase 6, and signal-induced proliferation-associated gene 1-and a down-regulation of the IL-17 precursor; tumor necrosis factor-related apoptosis-inducing ligand family member-associated nuclear factor-kappaB activator-binding kinase 1; and Golgi S-nitroso-N-acetylpenicillamine in cells treated with DcR3, further demonstrating its effect on DC differentiation and function.
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PMID:Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication. 1463 66

In the hope of identifying agents of therapeutic value in tissue inflammation, we tested ethanolic extracts of six Chinese herbs for their effects on human peripheral blood mononuclear cells (PBMC) proliferation in vitro. The results indicated that the extracts from Nelumbo nucifera Gaertn, used in treatment of tissue inflammation in traditional Chinese medicine, inhibited PBMC proliferation activated with phytohemagglutinin (PHA). By a bioassay-guided fractionation procedure, NN-B-4 identified from N. nucifera ethanolic extracts significantly suppressed activated PBMC proliferation. The inhibitory action of NN-B-4 did not involve direct cytotoxicity. In an attempt to further localize the point in the PBMC proliferation where arrest occurred, a set of key regulatory events leading to the cell proliferation, including cell cycle progression, production and gene expression of interleukin-2 (IL-2), IL-4, IL-10, and interferon-gamma (IFN-gamma) was examined. Cell cycle analysis indicated that NN-B-4 arrested the cell cycle progression of activated PBMC from the G1 transition to the S phase. The cyclin-dependent kinase (cdk) 4 mRNA expression in PBMC stimulated with PHA was reduced by NN-B-4. NN-B-4 suppressed, in activated PBMC, the production and mRNA expression of IL-2, IL-4, IL-10, and IFN-gamma in a dose-dependent fashion. The suppressant effects of NN-B-4 on proliferation of PBMC activated by PHA therefore appear to be mediated, at least in part, through inhibition of early transcripts of PBMC, especially those of important IL-2, IFN-gamma, and cdk4 and arrest of cell cycle progression in the cells.
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PMID:The extracts from Nelumbo Nucifera suppress cell cycle progression, cytokine genes expression, and cell proliferation in human peripheral blood mononuclear cells. 1517 79


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