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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The E2F-family of transcripion factors exerts fascinating and contrasting functions in transcriptional repression and activation of genes regulating proliferation, apoptosis, and differentiation. E2F is principally regulated by its temporal association with retinoblastoma pocket protein (pRb) family members. In turn, pRb is regulated through phosphorylation by cyclin-dependent kinase (cdk). The activity of cdk is negatively regulated by cdk-inhibitors, exemplified by p16INK4a, p21CIP1, and p27KIP1. Therefore, positive and negative signaling events converge on E2F activity resulting in distinct growth-controling and apoptotic activities. Here we describe the immunocytochemical detection of E2F, genomic DNA, BrdU-incorporation, and mitosis in cardiomyoctes. A detailed protocol is given to illustrate this technique in primary heart muscle cells.
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PMID:E2F transcription factors and pRb pocket proteins in cell cycle progression. 1557 36

Histone deacetylase inhibitors (HDACis) inhibit tumor cell growth and survival, possibly through their ability to regulate the expression of specific proliferative and/or apoptotic genes. However, the HDACi-regulated genes necessary and/or sufficient for their biological effects remain undefined. We demonstrate that the HDACis suberoylanilide hydroxamic acid (SAHA) and depsipeptide regulate a highly overlapping gene set with at least 22% of genes showing altered expression over a 16-h culture period. SAHA and depsipeptide coordinately regulated the expression of several genes within distinct apoptosis and cell cycle pathways. Multiple genes within the Myc, type beta TGF, cyclin/cyclin-dependent kinase, TNF, Bcl-2, and caspase pathways were regulated in a manner that favored induction of apoptosis and decreased cellular proliferation. APAF-1, a gene central to the intrinsic apoptotic pathway, was induced by SAHA and depsipeptide and shown to be important, but not essential, for HDACi-induced cell death. Overexpression of p16(INK4A) and arrest of cells in G(1) can suppress HDACi-mediated apoptosis. Although p16(INK4A) did not affect the genome-wide transcription changes mediated by SAHA, a small number of apoptotic genes, including BCLXL and B-MYB, were differentially regulated in a manner consistent with attenuated HDACi-mediated apoptosis in arrested cells. We demonstrate that different HDACi alter transcription of a large and common set of genes that control diverse molecular pathways important for cell survival and proliferation. The ability of HDACi to target multiple apoptotic and cell proliferation pathways may provide a competitive advantage over other chemotherapeutic agents because suppression/loss of a single pathway may not confer resistance to these agents.
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PMID:Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. 1573 94

In vitro expansion of chondrocytes for tissue-engineering applications is limited by forms of growth arrest known as quiescence and replicative senescence. At the molecular level cyclin-dependent kinase inhibitors (CDKIs) are involved in mediating growth arrest in the G1 phase of the cell cycle. Using ribonuclease protection assays and immunocytochemical staining methods, we quantitatively analyzed expression profiles of G1 cell cycle inhibitors at the mRNA and protein levels. These inhibitors included the CDKIs of the CIP/KIP family (p21CIP1 p27KIP1, and p57KIP2) and the INK4 family (p15INK4b, p16INK4a, p18INK4c, and p19INK4d) as well as the retinoblastoma protein-family (pRb, p107, and p130) and the tumor suppressor p53. Analysis was carried out in proliferating, quiescent, and senescent states of primary cultures of adult human nasoseptal chondrocytes. The most pronounced effect (p < 0.0001) between cultures in proliferation and cultures in growth arrest was an increased expression of the CDKIs p57KIP2 and p15INK4b for quiescent growth arrest, and of p16INK4a, p15INK4b, and p57KIP2 for senescent growth arrest. Thus, these cell cycle inhibitors represent potential candidates for selective intervention to promote cellular multiplication of chondrocytes undergoing in vitro expansion for tissue-engineering applications. Possible methods of modulation include the targeted elimination of specifically identified cell cycle inhibitors by antisense technologies.
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PMID:In vitro expansion of human nasoseptal chondrocytes reveals distinct expression profiles of G1 cell cycle inhibitors for replicative, quiescent, and senescent culture stages. 1573 62

Although a number of studies have shown that vitamins K1, K2 and K3 exerted antitumor effects on various types of rodent- and human-derived neoplastic cell lines, it has not been examined whether or not vitamin K5 also possesses antitumor activity. In the present study, we examined the antitumor effects of vitamin K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of vitamin K5 not only in vitro but also in vivo. Vitamin K5 was shown to suppress the proliferation of PLC/PRF/5 cells at a concentration of 30 microM. By a flow cytometric analysis, it was shown that although vitamin K5 did not induce apoptosis on PLC/PRF/5 cells, it did induce G1 arrest on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that vitamin K5 markedly suppressed the growth of HCC tumors. Although protein expression levels of cyclin D1 and p16INK4a cyclin-dependent kinase (Cdk) inhibitor in HCC tumors were not decreased by vitamin K5 treatment, those of Cdk4 were reduced significantly by the treatment. Taken collectively, vitamin K5 could induce potent antitumor effects on HCC not only in vitro but also in vivo, at least in part by inducing G1 arrest of cell cycle through downregulation of Cdk4 expression. The results demonstrated here indicate that vitamin K5 may be a useful agent for the treatment of patients with HCC.
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PMID:In vitro and in vivo antitumor effects of vitamin K5 on hepatocellular carcinoma. 1580 26

Melanoma-associated germline mutations affecting the tumor suppressor and cyclin-dependent kinase (CDK) inhibitor, CDKN2A/p16INK4a, have been identified in over 100 melanoma-prone families worldwide. To predict the melanoma risk for carriers of specific mutations, mutant p16INK4a can be tested in biochemical and cellular assays. In most cases, p16INK4a mutations with predicted disease relation, due to segregation with melanoma, are functionally impaired in such assays. The N-terminal 24 base pair duplication of CDKN2A, however, encodes a p16INK4a variant previously shown to have wild-type function, despite segregating with melanoma in at least 5 melanoma families. To clarify whether the duplication mutation has a cell cycle regulatory defect or behaves like wild-type p16INK4a, we reanalyzed the cell cycle-inhibitory activity of this mutation. Stable cell clones of the p16-null WMM1175 melanoma cell line inducible for ectopic p16INK4a were used in this study. In these cells, p16INK4a expression can be controlled at physiologic levels. Our results show that in comparison to wild-type p16INK4a, the duplication mutant induced weaker S-phase inhibition and cells expressing this mutant form of p16INK4a retained colony formation ability. We also show that the cell cycle-regulatory defect of the p16INK4a duplication mutant was associated with decreased inhibition of pRb phosphorylation even though it retained significant binding to CDK4.
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PMID:The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired. 1594

CD4+CD25+ regulatory T cells (Tregs) are essential negative regulators of immune responses. Here, we examined the signaling properties of human Tregs, using CD4+CD25+ Treg and CD4+CD25- control (Tcont) cell lines generated from cord blood. Treg cell lines were markedly hyporesponsive to stimulation with dendritic cells and with anti-CD3/CD28-coated beads. Hyporesponsiveness was reversed by exogenous interleukin-2 (IL-2). T-cell receptor (TCR)-CD3/CD28-mediated activation of Rap1 and Akt was retained in Tregs, but activation of Ras, mitogenactivated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated kinase 1/2 (Erk1/2) was impaired. Tregs were blocked from cell cycle progression due to decrease of cyclin E and cyclin A and increase of p27kip1 (p27kip cyclin dependent kinase inhibitor). IL-2 induced sustained increase of cyclin E and cyclin A and prevented up-regulation of p27kip1. Tregs had high susceptibility to apoptosis that was reversed by IL-2, which correlated with activation of Erk1/2, up-regulation of Bcl-x(L) (B-cell CLL/lymphoma 2-like nuclear gene encoding mitochondrial protein, transcript variant 2), and phosphorylation of Bad (Bcl2 antagonist of cell death) at Ser112. Thus, Tregs share biochemical characteristics of anergy, including abortive activation of Ras-MEK-Erk, increased activation of Rap1, and increased expression of p27kip1. In addition, our results indicate that TCR-CD3/CD28-mediated and IL-2 receptor-mediated signals converge at the level of MEK-Erk kinases to regulate Treg survival and expansion and suggest that manipulation of the MEK-Erk axis may represent a novel strategy for Treg expansion for immunotherapy.
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PMID:CD4+CD25+ regulatory T-cell lines from human cord blood have functional and molecular properties of T-cell anergy. 1602 May 8

Corneal endothelium is the single-cell layer that forms a physical barrier between the corneal stroma and aqueous humour. The barrier and ionic 'pump' functions of corneal endothelium help regulate stromal hydration. Loss of endothelial cells due to increasing age, trauma, disease, dystrophy, or previous corneal transplants can reduce the density of endothelial cells to a critical point below which the stroma becomes edematous and visual acuity is lost. Throughout life, division of endothelial cells either does not occur or occurs at a rate too slow to adequately replace dead cells. Thus, the major means of repairing the monolayer is by cell migration and/or enlargement. The basis for the lack of endothelial cell proliferation is not yet fully understood, although it is clear that cells do retain proliferative capacity. Previous studies from this laboratory have identified certain environmental conditions that may be responsible for maintaining these cells in a non-replicative state in vivo. In addition, corneal endothelial cells exhibit intrinsic, age-related differences in relative proliferative capacity. The studies described below provide evidence to support the hypothesis that, with age, an increasing number of HCEC enter a replicative senescence-like state in which they become increasingly refractive to mitogenic stimulation. This decreasing sensitivity to mitogens appears to be mediated, at least in part, by age-dependent alterations in the relative expression and activity of the cyclin-dependent kinase inhibitors, p27KIP1, p16INK4A, and p21CIP1.
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PMID:Cell cycle status in human corneal endothelium. 1605 24

p16INK4a is a cyclin-dependent kinase (CDK) inhibitor which decelerates cell cycle by inactivating CDKs that phosphorylate pRb. Human Papillomavirus persistent infection plays an important role on cervical carcinogenesis, mainly by the action of two viral oncoproteins, E6 and E7, which interact with p53 and pRb, respectively. Increasing expression of E6 and E7 in dysplastic cervical cells might thus be reflected by increased expression of p16INK4a. Recent studies revealed that p16INK4a expression could be a marker for dysplastic and neoplastic cervical cells. The aim of this study was to analyze p16INK4a expression in cervical preneoplastic and neoplastic lesions and correlate with lesion grade. Expression of p16INK4a was analyzed by immunohistochemistry. A total of 6 low-grade squamous intraepithelial lesion (LSIL), 21 high-grade squamous intraepithelial lesions (HSIL) and 27 cancer samples were studied. In HPV-positive cervical samples (n=48), p16INK4a expression was observed in 1 of 3 LSIL, in 18 of 19 HSIL and in all 26 cancer cases. These results are in accordance with the hypothesis that functional inactivation of pRb by HPV-E7 protein induces p16INK4a expression in cervical lesions. In our study, a statistically significant association was observed between cervical lesion grade and p16INK4a expression (P<0.001).
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PMID:p16INK4A expression in cervical premalignant and malignant lesions. 1625 3

Carcinoma of the uterine cervix is one of the most common malignancies among women worldwide. Human papillomaviruses (HPV) have been identified as the major etiological factor in cervical carcinogenesis. However, the time lag between HPV infection and the diagnosis of cancer indicates that multiple steps, as well as multiple factors, may be necessary for the development of cervical cancer. The development and progression of cervical carcinoma have been shown to be dependent on various genetic and epigenetic events, especially alterations in the cell cycle checkpoint machinery. In mammalian cells, control of the cell cycle is regulated by the activity of cyclin-dependent kinases (CDKs) and their essential activating coenzymes, the cyclins. Generally, CDKs, cyclins, and CDK inhibitors function within several pathways, including the p16(INK4A)-cyclin D1-CDK4/6-pRb-E2F, p21(WAF1)- p27(KIP1)-cyclinE-CDK2, and p14(ARF)-MDM2-p53 pathways. The results from several studies showed aberrant regulation of several cell cycle proteins, such as cyclin D, cyclin E, p16(INK4A), p21(WAF1), and p27(KIP1), as characteristic features of HPV- infected and HPV E6/E7 oncogene-expressing cervical carcinomas and their precursors. These data suggested further that interactions of viral proteins with host cellular proteins, particularly cell cycle proteins, are involved in the activation or repression of cell cycle progression in cervical carcinogenesis.
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PMID:Aberrant cell cycle regulation in cervical carcinoma. 1625 56

In breast cancer, cyclins D1 and E and the cyclin-dependent kinase inhibitors p21 (Waf1/Cip1)and p27 (Kip1) are important in cell-cycle control and as potential oncogenes or tumor suppressor genes. They are regulated in breast cancer cells following mitogenic stimuli including activation of receptor tyrosine kinases and steroid hormone receptors, and their deregulation frequently impacts on breast cancer outcome, including response to therapy. The cyclin-dependent kinase inhibitor p16 (INK4A) also has a critical role in transformation of mammary epithelial cells. In addition to their roles in cell cycle control, some of these molecules, particularly cyclin D1, have actions that are not mediated through regulation of cyclin-dependent kinase activity but may be important for loss of proliferative control during mammary oncogenesis.
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PMID:Cell cycle control in breast cancer cells. 1626 37


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