Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The INK4 locus has two promoters and encodes two unique proteins that share exons in different reading frames, p16(INK4a) and p14(ARF). The p16(INK4a) protein, by inhibiting cyclin-dependent kinase, down regulates Rb-E2F and leads to cell cycle arrest in the G1 phase. The p14(ARF) protein interacts with the MDM2 protein, neutralizing MDM2-mediated degradation of p53. Since p53/Rb genes are not altered in malignant mesothelioma, additional components of these pathways, such as p16(INK4a) and p14(ARF), are candidates for inactivation. In this study, we have examined p16(INK4a) and p14(ARF) alterations (gene deletion, mutation and promoter methylation) in 45 primary malignant mesothelioma specimens. Fourteen patients (31%) had altered p16; four tumors had a methylated promoter region (8.8%), 10 tumors showed p16 to be deleted (22.2%), and one tumor had a point mutation (2%). We did not find any instances of methylation in the p14(ARF) 5'-CpG island. Patients whose tumors had p16 deletion were significantly younger than those with methylation, and, in the patients whose lungs were studied for the prevalence of asbestos fibers, those with any p16 alteration had lower fiber counts than those with no p16 alteration. Hence, p16 gene alteration is relatively common in malignant mesothelioma, while p14(ARF) is rarely, if ever, methylated. Our data suggest that deletion of p16 occurs in a relatively susceptible subset of the population.
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PMID:Alterations of the p16(INK4) locus in human malignant mesothelial tumors. 1211 69

Intracranial ependymomas are the third most common primary brain tumor in children. Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on immunohistochemistry of ependymomas has been reported in a few studies. One-hundred and twelve patients with intracranial ependymomas were examined retrospectively for immunoexpression of various tumor-associated antigens and apoptosis. The results demonstrated significant preponderance of expression of the tenascin, vascular endothelial growth factor protein (VEGF), epidermal growth factor (EGFR) and p53 protein in high-grade tumors. Also high-grade ependymomas revealed more prominent labeling indices (LI) for proliferative marker Ki-S1 and apoptotic index (AI), and lower LI for cyclin-dependent kinase inhibitors p27/Kipl and pl4ARF. For low-grade ependymomas the progression-free survival time (PFS) was found to be significantly shorter for Ki-S1 LI > 5%, and for tenascin, VEGF and EGFR positivity. For high-grade ependymomas PFS was found to be significantly reduced for p27 LI < 20%, p14ARF LI < 10%, for p53 positivity, and for AI < 1%. The CART modeling process exhibited five final groups of ependymoma patients (1) low-grade and tenascin-negative; (2) low-grade and tenascin-positive; (3) high-grade and p53-negative with p14 LI > 0%; (4) high-grade with combination of either p53 positivity and p14 LI > 10% or p53 negativity and p14 LI < 10%; (5) high-grade and p53-positive with pl4 LI < 10%. In summary, some immunohistochemical variables were found to be the strong predictors of ependymoma recurrence and they seem to be useful for assessing individual tumor prognosis in routinely processed biopsy specimens together with tumor grade. For histologically benign ependymomas immunohistochemical study should be focused on Ki-S1, tenascin, EGFR and VEGF evaluation, whereas p53 expression and number of p27, p14 and ISEL-positive nuclei will be of value in determining PFS from high-grade ependymomas.
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PMID:Immunohistochemical markers for prognosis of ependymal neoplasms. 1218 59

The transcription factor E2F-1 induces cell cycle progression at the G1/S checkpoint, and deregulation of E2F-1 provokes apoptosis in a wide variety of malignant cells. To date only p14(ARF) and p73, a p53 homologue, have been identified as E2F-1-inducible genes capable of mediating an apoptotic response. Here we show that adenovirus-mediated E2F-1 overexpression in cancer cells induces expression and autophosphorylation of the double-stranded RNA-dependent protein kinase PKR leading to phosphorylation of its downstream target, the alpha-subunit of the eukaryotic translation initiation factor 2 (eIF-2alpha) and to apoptotic cell death. This PKR-dependent apoptosis occurs in cell lines with mutated p53 and in cell lines with mutated p53 and p73, and is significantly reduced by the chemical inhibition of PKR activation. Further, PKR(-/-) mouse embryo fibroblasts, but not PKR(+/+) mouse embryo fibroblasts, demonstrate significant resistance to E2F-1-induced apoptosis. We conclude that an important pathway of E2F-1-mediated apoptosis is dependent on PKR activation and does not require p53 or p73.
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PMID:Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis. 1221 68

Using an estrogen-inducible retroviral system, we demonstrate that oncogenic Raf-1 induces growth arrest and morphological changes in finite lifespan human mammary epithelial cells (HMEC). This arrest does not rely on expression of the cyclin-dependent kinase inhibitor (CKI) p16(INK4a), nor on changes in expression of the CKIs p21(Cip1), p14(ARF), p27(Kip1) or p57(Kip2). The Raf-induced arrest is independent of viral oncogene mediated inactivation of p53 and pRB, or c-myc overexpression. Flow cytometric analysis demonstrates that cells arrest in both G1 and G2. The Raf-induced arrest is mitigated or eliminated in some immortally transformed HMEC. Immortal HMEC that have both overcome replicative senescence and undergone the recently described conversion process maintain growth in the presence of transduced oncogenic Raf-1; they also gain EGF-independent growth and a low frequency of anchorage-independent growth. However, HMEC that have overcome replicative senescence but have not undergone conversion and HMEC immortalized by transduction with the catalytic subunit of telomerase, hTERT, remain severely growth arrested. These results indicate that the molecular mechanisms responsible for the Raf-1-induced growth arrest may vary among different finite lifespan cell types, and that in HMEC, this mechanism is altered during the conversion process, rather than as a direct consequence of overcoming senescence or expressing hTERT.
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PMID:Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion. 1221 73

The human Ink4a/Arf tumor suppressor locus encodes two distinct products: p16(Ink4a) which prevents phosphorylation and inactivation of the retinoblastoma protein and, p14(Arf), a nucleolar protein which activates the function of the tumor suppressor p53 protein in the nucleoplasm in response to oncogenic stimulation through an as yet ill-defined mechanism. Here we show that the level of endogenous p14(Arf) and its balance between the nucleolus and the nucleoplasm in HeLa cells are exquisitely sensitive to changes in cell morphology and to short-lived perturbations in cell cycle and in nucleolar function such as those induced by the cyclin-dependent kinase inhibitor, roscovitine, and the casein kinase II and RNA synthesis inhibitor, DRB. Most remarkably, whereas p14(Arf) predominantly concentrates in the nucleolus of interphase cells and transiently disappears between metaphase and early G1 under normal growth conditions, it massively and reversibly accumulates in the nucleoplasm of postmitotic and S-phase cells upon short-term treatment with roscovitine and, at a lesser extent, DRB. In line with the fact that the nuclear level of p53 reaches a peak between mid-G1 and the G1/S border in p53-expressor cells which lack Arf expression, these results provide a clue that, in p53+/Arf+ cells, Arf proteins might serve both to speed and to amplify p53-mediated responses in conditions and cell cycle periods in which the mechanisms involved in p53 stabilization and activation are not fully operational. They further suggest that human endogenous p14(Arf) might activate p53 pathways in physiologic situations by acting inside the nucleoplasm, especially when normal cell cycle progression and nucleolar function are compromised.
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PMID:Human p14(Arf): an exquisite sensor of morphological changes and of short-lived perturbations in cell cycle and in nucleolar function. 1236 Apr 4

Cellular replicative senescence is a permanent growth arrest state that can be triggered by telomere shortening. The cyclin-dependent kinase (Cdk) inhibitor p21(CIP1/WAF1) (p21), encoded by the CDKN1A gene, is a critical cell cycle regulator whose expression increases as cells approach senescence. Although the pathways responsible for its up-regulation are not well understood, compelling evidence indicates that the upstream triggering event is telomere dysfunction. Studies of replicative senescence have been complicated by the asynchrony of its onset, which is caused by the continuous and stochastic variability in individual cell lifespans. In fact, the actual entry into senescence has never been observed in a single unperturbed cell. We report here a new in vitro human model system that allows entry into senescence to be monitored in real-time in individual viable cells. We used homologous recombination to generate non-immortalized fibroblast cells with the enhanced yellow fluorescence protein (EYFP) gene knocked into one CDKN1A gene copy, allowing promoter activity to be visualized as fluorescence intensity. Gamma irradiation, DNA-damaging drugs, expression of p14(ARF) or oncogenic Ras, and replicative exhaustion all resulted in elevated EYFP expression, demonstrating its proper control by physiological signalling circuits. Analysis by time-lapse microscopy of cultures approaching replicative senescence revealed that p21 levels rise abruptly in individual aging cells and remain elevated for extended periods of time.
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PMID:Real-time imaging of transcriptional activation in live cells reveals rapid up-regulation of the cyclin-dependent kinase inhibitor gene CDKN1A in replicative cellular senescence. 1467 32

In standard conditions of tissue culture, human fibroblasts undergo a limited number of population doublings before entering a state of irreversible growth arrest termed replicative senescence or M1. The arrest is triggered by a combination of telomere dysfunction and the stresses inflicted by culture conditions and is implemented, at least in part, by the cyclin-dependent kinase inhibitors p21(CIP1) and p16(INK4a). To investigate the role of p16(INK4a), we have studied fibroblasts from members of melanoma prone kindreds with mutations in one or both copies of the CDKN2A locus. The mutations affect the function of p16(INK4a) but not of the alternative product, p14(ARF). The p16(INK4a)-defective fibroblasts have an above average life span, compared to the heterozygous and normal age-matched controls, but they arrest with characteristics typical of senescence. Using agents that are known to bypass M1, such as DNA tumor virus oncoproteins or the Bmi1 transcriptional repressor, we provide evidence that p16(INK4a) defective cells arrest at a stage that is operationally between M1 and M2 (crisis). As well as indicating that p16(INK4a) contributes to but is not essential for replicative senescence of human fibroblasts, our data reveal considerable heterogeneity in the levels and accumulation of p16(INK4a) in different strains.
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PMID:Contribution of p16(INK4a) to replicative senescence of human fibroblasts. 1526 1

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

Two functionally and structurally different proteins, p16(INK4a) and p14(ARF), encoded by the gene INK4a/ARF located at 9p21 are cyclin-dependent kinase (cdk) inhibitors and important cell cycle regulators. More and more evidences have been accumulated to show that the exogenous p16(INK4a) or p14(ARF) can inhibit the cell growth and/or induce the apoptosis. But it is still unclear if they can play positive role when combine with the conventional chemotherapy in cancer treatment. Here we show that cationic liposome-mediated gene transfection of INK4a/ARF into lung cancer cell line A549, in which the INK4a/ARF locus was lost, suppressed the growth and induced apoptosis. When treated with five different chemotherapy drugs with different mechanism after the transfection, A549 got an increased chemosensitivity for adriamycin and cisplatin and an unchanged result for topotecan, taxol or vinorelbine. The results indicated that cell cycle redistribution and increased apoptosis index after transfection might be the main explanation for the enhanced chemosensitivity. The combination of gene therapy with conventional chemotherapy is not always better than single chemotherapy. This trial will be of benefit to the treatment of lung cancer when combine the conventional chemotherapy and gene therapy in the future.
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PMID:The co-transfection of p16(INK4a) and p14(ARF) genes into human lung cancer cell line A549 and the effects on cell growth and chemosensitivity. 1633 11

Hypermethylation of CpG islands within the promoter region is one of the mechanisms by which genes are inactivated and may be one of the reason for silencing of cell cycle control or DNA-mismatch repair genes in myelodysplastic syndrome (MDS). Since the function of cell cycle control genes including the cyclin-dependent kinase inhibitors known as p15(INK4b) and p16(INK4a), as well as p14(ARF) which blocks MDM-2 (an inhibitor of p53), the retinoblastoma (RB1) protein and the mismatch repair gene MGMT is critical for hematopoietic proliferation and differentiation, we performed methylation specific polymerase chain reaction (MSP) in low-density, non-adherent bone marrow cells from 49 patients with MDS. In addition, expression of p15(INK4b) and RB1 was analysed by quantitative real-time PCR. From selected patients, we analyzed the methylation pattern of cell cycle control genes in CD34+ bone marrow cells. Thirty-nine of 49 cases (80%) had at least one of five genes methylated in our MDS samples by analysing low-density non-adherent bone marrow cells. The frequency of p15(INK4b) methylation was 34 of 49 samples (69%). The incidence of methylation of both p14(ARF) and p16(INK4a) was four of 49 (8%). RB1 gene was methylated in seven samples (14%) and each patient had RA. Interestingly, none of these genes were methylated in the purified CD34+ hematopoietic stem cells from the MDS patients. Furthermore, all our RARS patients had a methylated p15(INK4b) promoter correlating with non-detectable expression of this gene in bone marrow cells from those patients. These results indicate that hypermethylation of cell cycle control genes in MDS may occur late during the differentiation of myelodysplastic stem cells.
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PMID:Comparative analysis of hypermethylation of cell cycle control and DNA-mismatch repair genes in low-density and CD34+ bone marrow cells from patients with myelodysplastic syndrome. 1668 76


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