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)

Abnormal control of the cell cycle is closely linked to carcinogenesis. p21WAF1/CIP1 protein is a universal inhibitor of G1 cyclin-dependent kinase and is induced by p53-dependent and -independent pathways. In order to elucidate the role of p21WAF1/CIP1 in human skin carcinogenesis, protein expression in squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Bowen's disease (BD), actinic keratosis (AK), keratoacanthoma (KA), seborrheic keratosis (SK), and normal skin was examined using an immunohistochemical method. In normal skin, a few positive cells were seen in some cases in the upper spinous layer of the epidermis; sebaceous glands also had positive cells. In cases of SK and KA, positive cells were found in the basal and suprabasal epidermal layers (proliferation pattern), and in cases of BD and AK, positive cells were seen mainly in the upper spinous layer (differentiation pattern). Cases of SCC had more positive cells and showed two staining patterns: proliferation, or mixed. Cases of BCC had no positive cells. p21WAF1/CIP1 has some unidentified role in keratinocyte tumorigenesis, which may not be related directly to carcinogenesis.
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PMID:p21WAF1/CIP1 expression in non-melanoma skin tumors. 913 13

The p16 (MTS1) tumour-suppressor gene is a cyclin-dependent kinase (cdk) inhibitor that decelerates the cell cycle by inactivating the cdks that phosphorylate the retinoblastoma tumour-suppressor gene (Rb) protein (pRb). In cervical cancers, pRb is inactivated by the HPV E7 oncoprotein or by mutations. The hypothesis of earlier reports was that the disruption of the p16/cdk-cyclin/Rb cascade is essential for malignant cervical transformation/carcinogenesis. We previously established in vitro model systems of cervical cancer representing four steps of oncogenic progression initiated by the two most common oncogenic HPVs in ectocervical and endocervical epithelial cells. This report used these systems to investigate the role of p16 in cervical cancers. A dramatic enhancement of the p16 RNA level was observed after immortalization by HPV 16 or 18. Furthermore, the p16 protein was newly observed following immortalization. However, no further changes were found for RNA or protein levels after serum selection or malignant transformation. For three cervical carcinoma cell lines, similar high levels of p16 expression were seen. Point mutations or homozygous deletions of p16 were not observed in the in vitro systems or in clinical specimens. These results suggest that the inactivation of the p16/cdk-cyclin/Rb cascade does not occur during malignant transformation but occurs during the immortalization by HPV in HPV-harbouring premalignant lesions, the in situ equivalent of immortalized cells. Also suggested is that p16 has no role in the specific malignant transformation step from immortal premalignant lesions during the carcinogenesis of HPV-initiated cervical cancers.
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PMID:Induction of p16 during immortalization by HPV 16 and 18 and not during malignant transformation. 916 31

During the past years the elucidation of cell cycle regulation has revolutionized our understanding of cancer development. Many new genes have been identified which promote genetic instability when mutated. They encode cyclins, inhibitors of cyclin-dependent kinases (CDKs) or other cell cycle regulators. The regulation of the CDK activities in different phases of the cell cycle controls the correct process of DNA synthesis and replication. Complex signal transduction systems, so-called checkpoints, regulate growth arrest, DNA repair and programmed cell death (apoptosis) and thereby prevent the formation of tumour cells. An overview is presented on the molecular mechanisms of cell cycle control and their significance for genetic stability. The functions of proto-oncogenes (e.g., c-myc) and tumour-suppressor genes (e.g., p53) in this context is described. In particular, recent advances in the understanding of skin carcinogenesis, the role of UV radiation and cancer therapy are discussed.
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PMID:[Cell cycle control, genetic instability and cancer]. 918 85

(-)-Epigallocatechin gallate (EGCG) and theaflavins are believed to be key active components in tea for the chemoprevention against cancer. However, the molecular mechanisms by which EGCG and theaflavins block carcinogenesis are not clear. We have used the JB6 mouse epidermal cell line, a system that has been used extensively as an in vitro model for tumor promotion studies, to examine the anti-tumor promotion effects of EGCG and theaflavins at the molecular level. EGCG and theaflavins inhibited epidermal growth factor- or 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation in a dose-dependent manner. At the dose range (5-20 microM) that inhibited cell transformation, EGCG and theaflavins also inhibited AP-1-dependent transcriptional activity and DNA binding activity. The inhibition of AP-1 activation occurs through the inhibition of a c-Jun NH2-terminal kinase-dependent, but not an extracellular signal-regulated protein kinase (Erk) 1-dependent or Erk2-dependent, pathway. Because the transcription factor AP-1 is important for tumor promoter-induced neoplastic transformation, the inhibitory effects on AP-1 activation by EGCG and theaflavins may further explain the anti-tumor promotion action of these tea constituents.
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PMID:Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (-)-epigallocatechin gallate, and theaflavins. 933 Nov 5

To study the altered mechanisms of cell cycle regulation in colorectal cancer, the expressions of cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, p53 and retinoblastoma (Rb) protein were analyzed by western blotting in a series of human colorectal cancer cell lines. The colorectal cancer cell lines exhibited various expression patterns of cell cycle regulators, which may reflect differences in the biological characteristics of cancer cells and in the genetic backgrounds of carcinogenesis. A correlation was found between p53 gene alteration and p21 expression, suggesting that p53 gene mutation usually suppresses p21 expression, though p21 expression could be induced via both a p53-dependent and a p53-independent pathway in colorectal cancer. None of the cell lines studied expressed p16 protein, suggesting that inactivation of p16 may be a common alteration in colorectal cancer. Moreover, all the D-type cyclins, especially D2 and D3, were expressed at a high level in most of the cell lines. Loss of p16 expression and increased expression of D-type cyclins promote CDK-mediated Rb phosphorylation. All of the colorectal cancer cell lines studied herein expressed Rb protein, but the growth-suppressive properties of Rb may be inactivated by the loss of p16 expression and increased expressions of D-type cyclins. In view of the pivotal role of Rb in cell cycle regulation, loss of p16 expression and overexpression of D-type cyclins may be critical alterations in colorectal cancer.
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PMID:Expressions of cell cycle regulators in human colorectal cancer cell lines. 936 33

Dietary energy restriction was previously shown to be effective in preventing a wide range of experimentally induced cancers. Studies were conducted to assess the influence on pancreatic carcinogenesis of dietary energy restrictions (reduced fat and carbohydrate) of 10%, 20% or 40% in comparison with control in Syrian hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Two carcinogenesis studies were conducted. One used a single treatment with 20 mg BOP/kg body weight and followed hamsters for 102 weeks following treatment, and the other used three weekly treatments of 20 mg BOP/kg body weight and followed hamsters for 45 weeks after treatment. Hamsters were fed control or energy restricted diet beginning the week following the last BOP treatment. Pancreatic carcinomas were induced in 9-18% of the hamsters in the first experiment and in 59-66% of the animals in the second. Dietary energy restriction did not influence carcinoma incidence in either study, and in the second experiment the multiplicity of tumors was higher in the 40% energy restriction (ER) group than in control hamsters. Plasma corticosterone was suppressed by BOP treatment, particularly in the 20% and 40% ER hamsters in the second experiment, and diet or BOP treatment did not significantly alter plasma cortisol. Pancreatic protein kinase Czeta measured by Western blot was highest in the cytosol and particulate fractions of the 40% ER hamsters in the first experiment. These results indicate that dietary energy restriction is not effective in the prevention of BOP induced pancreatic carcinogenesis in the Syrian hamster.
Carcinogenesis 1997 Nov
PMID:Dietary energy restriction does not inhibit pancreatic carcinogenesis by N-nitrosobis-2-(oxopropyl)amine in the Syrian hamster. 939 9

Lung cancer is the most common cause of cancer death in Japanese males, the incidence having increased markedly in recent years. Carcinogen exposure such as to tobacco-smoke and air pollution are associated with the probability of developing lung cancer. Aquired somatic mutations play an important role in the pathogenesis of environmentally induced lung cancers. Cytogenetic and molecular analysis of lung tumors has made it possible to examine this hypothesis and to search for candidate genes that may be targeted by chronic exposure to these carcinogens. Early studies implicate several distinct chromosomal loci (3p, 9p, 13q, 17p, and others) and suggest sequential genetic events occur during the initiation and progression of lung carcinogenesis. Several suppressor genes including Rb (13q), P53 (17p), and P16 (9p) have been identified and cloned at these chromosomal loci. The identification of putative tumor suppressor gene at chromosome 3p is still under work. Understanding the interaction of P53, RB, cyclins, and protein kinase inhibitors including P16 will be essential to the development of the next generation of diagnostic and therapeutic studies for lung cancer.
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PMID:Tumor suppressor genes in human lung cancer. 939 13

Recent studies have shown that the cyclin-dependent kinase (cdk) inhibitors play important roles in cell cycle progression in normal cells. Alterations in the cdk inhibitors also appear to be important in cancer development in a number of human tumors. p27Kip1 is a member of the CIP/KIP family of cdk inhibitors that negatively regulates cyclin-cdk complexes. Reduced levels of p27Kip1 protein have been identified in a number of human cancers, and in some cases reduced p27Kip1 is associated with an increase in proliferative fraction. In the present study, we examined p27Kip1 protein by immunohistochemistry in 10 normal and 36 dysplastic epithelia and in 8 squamous cell carcinomas from one anatomical site within the oral cavity, the floor of the mouth. Proliferative activity was assessed in serial sections by determining the expression of the cell cycle proteins Ki-67 and cyclin A. p27kip1 protein was significantly reduced in oral dysplasias and carcinomas compared with that in normal epithelial controls. In addition, there was a significant reduction in p27Kip1 protein between low- and high-grade dysplasias, suggesting that changes in p27Kip1 expression may be an early event in oral carcinogenesis. There was increasing expression of Ki-67 and cyclin A proteins with increasingly severe grades of dysplasia compared with normal controls. Although there was a strong correlation between Ki-67 and cyclin A scores (r2= 0.61) for all categories of disease, there was a weak negative correlation between Ki-67 and p27Kip1 levels (r2 = 0.29) and between cyclin A and p27Kip1 levels (r2 = 0.25). In conclusion, this study has found that a reduction in the proportion of cells expressing p27Kip1 protein is frequently associated with oral dysplasia and carcinoma from the floor of the mouth. Furthermore, reductions in p27Kip1 levels are associated with increased cell proliferation, although other changes likely contribute to altered cell kinetics during carcinogenesis at this site.
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PMID:Reduced levels of the cell-cycle inhibitor p27Kip1 in epithelial dysplasia and carcinoma of the oral cavity. 946 85

The molecular events regulating the development and progression of colonic neoplasia are currently being delineated. Recent studies have implicated c-Src protein kinase activation as an early event in the malignant transformation of colonic epithelial cells. However, increased c-Src activity has also been reported in colon carcinomas as well as in metastatic hepatic and extrahepatic colon carcinomas. To further investigate the potential role of c-Src in the progression of colonic neoplasia, we analyzed c-Src levels by immunohistochemistry in 27 colorectal resection specimens. Mouse monoclonal antibody to c-Src protein was applied to 3-micron sections from formalin-fixed, paraffin-embedded tissues using the avidin-biotin-peroxidase method. The combination of adenomatous (AD) and adjacent carcinomatous mucosa (CA) specimens were present in 20 of 27 patients. In 15 cases, synchronous metastatic (MT) lesions were available for evaluation. Strong c-Src expression was evident in 95% of AD (n = 20), in contradistinction to 32% of MT (n = 19) and 14% of CA (n = 22). Weak-to-moderate c-Src expression was seen in adjacent normal colonic mucosa (NM) in 96% of cases. Signed rank test univariate analysis revealed a statistically significant difference in c-Src expression between NM/AD (p = 0.0001), NM/CA (p = 0.0001), NM/MT (p = 0.0006), AD/CA (p = 0.0001), and AD/MT (p = 0.0002). No significant correlation between levels of c-Src expression and patient survival, tumor size, histologic grade, or tumor configuration was observed using the Cox's Regression Model. Similar results were obtained by analysis of c-Src protein levels and c-Src kinase activity as measured by Western blot and in vitro kinase assays of representative cases. Our results indicate that: (a) elevated c-Src expression is an important early event during colorectal carcinogenesis; (b) its activation may be involved in tumor progression in a subset of colonic carcinomas; and (c) additional molecular events are necessary for invasion to occur.
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PMID:Elevated c-Src protein expression is an early event in colonic neoplasia. 952 Sep 49

Cyclic AMP (cAMP) is an important regulator of liver growth and differentiation. The main intracellular cAMP receptor, cAMP-dependent protein kinase (PKA), consists of two regulatory (R) and two catalytic (C) subunits. There are two classes, RI and RII, of the regulatory subunit, giving rise to type I (RI2C2) and type II (RII2C2) PKA. The RI/RII ratio generally decreases during organ development, and increases during carcinogenesis. Alterations in this ratio have been implicated as an important factor in experimental and clinical carcinogenesis. We have studied the expression of RIalpha, RIIalpha, Calpha, and an important substrate of PKA, the cAMP-response element binding protein, during rat liver carcinogenesis. Two-color immunofluorescence and confocal laser scan microscopy were used to characterize localization of the cAMP-dependent signal transducers in hepatocytes, bile ducts, oval cells, and preneoplastic lesions. We found that bile ducts and oval cells (putative liver stem cells) contained a higher RI/RII ratio than hepatocytes and preneoplastic lesions. Thus, an altered RI/RII ratio was not detected during early rat liver carcinogenesis, but may contribute to differentiation of putative liver stem cells to hepatocytes.
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PMID:Localization of cAMP-dependent signal transducers in early rat liver carcinogenesis. 954 68


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