Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G1 phase progression of mammalian cells is mainly controlled by the cyclin-cyclin-dependent kinase (CDK)-CDK inhibitor-retinoblastoma protein (pRb) regulatory pathway. Cell cycle regulators controlling G1 phase progression are frequently involved in the carcinogenesis of many human cancer types. In hepatocellular carcinoma (HCC) the CDK inhibitor p16INK4 is predominantly inactivated by post-transcriptional regulation and p16INK4 inactivation participates in the early-stage of hepatocarcinogenesis and in disease progression. Reduced p21(WAF1/CIP1) expression, which is associated mainly with p53 gene mutation in HCCs, contributes to hepatocarcinogenesis. Reduced p27Kip1 expression is also frequently involved in HCC. The CDK inhibitors p16INK4, p21(WAF1/CIP1) and p27Kip1 are independently affected and a change in the expression of one or more of these inhibitors contributes to carcinogenesis of the majority (nearly 90%) of HCCs. Cyclin D1 amplification and overexpression play a role in the carcinogenesis of a subset (11-13%) of HCCs. Disruption of the regulatory system controlling G1 phase progression is a common event in human hepatocarcinogenesis. Further studies systematically analyzing the major regulators controlling G1 phase progression in a large cohort of HCCs will strengthen our understanding of the molecular mechanism underlying human hepatocarcinogenesis. Correcting alterations that have occurred in the G1 phase regulatory machinery may provide a novel weapon to treat and prevent HCC.
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PMID:Cell cycle regulators and human hepatocarcinogenesis. 984 Jan 20

Cell proliferation is regulated by the cell cycle which is controlled by a number of cyclin-dependent kinases (CDKs). The functions of CDKs are critical for cell cycle and are required to traverse checkpoints. A network of inhibitors (CKI) of the cyclin-dependent kinases provide the important function of regulating the activity of the cyclin complexes. Deregulation of these results in either uncontrolled proliferation or cell death (apoptosis). Cell proliferation is an important factor in the development of carcinogenesis induced by genotoxic as well as nongenotoxic carcinogens. It is an integral part of the process of converting DNA adducts to mutations, it also decreases the time that is available for DNA repair and is required to clonal expansion of initiated cell populations. Moreover, cell proliferation increases the number of initiated cells by blocking cell death (apoptosis) and pertrubing checkpoints in the cell cycle. Two major mechanisms of induction of cell proliferation (regenerative and mitogens-stimulated) were discussed in relation to their potential roles in the carcinogenicity.
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PMID:[The role of cell proliferation in carcinogenesis]. 993 19

Telomerase is a ribonucleoprotein enzyme that adds hexanucleotide repeats TTAGGG to the ends of chromosomes. Telomerase activation is known to play a crucial role in cell-immortalization and carcinogenesis. Telomerase is shown to have a correlation with cell cycle progression, which is controlled by the regulation of cyclins, cyclin dependent kinases (cdks) and cyclin dependent kinase inhibitors (cdkis). Abnormal expression of these regulatory molecules may cause alterations in cell cycle with uncontrolled cell growth, a universal feature of neoplasia. Skin cancer is the most prevalent form of cancer in humans and the solar UV radiation is its major cause. Here, we investigated modulation in telomerase activity and protein expression of cell cycle regulatory molecules during the development of UVB-induced tumors in SKH-1 hairless mice. The mice were exposed to 180 mjoules/cm2 UVB radiation, thrice weekly for 24 weeks. The animals were sacrificed at 4 week intervals and the studies were performed in epidermis. Telomerase activity was barely detectable in the epidermis of non-irradiated mouse. UVB exposure resulted in a progressive increase in telomerase activity starting from the 4th week of exposure. The increased telomerase activity either persisted or further increased with the increased exposure. In papillomas and carcinomas the enzyme activity was comparable and was 45-fold higher than in the epidermis of control mice. Western blot analysis showed an upregulation in the protein expression of cyclin D1 and cyclin E and their regulatory subunits cdk4 and cdk2 during the course of UVB exposure and in papillomas and carcinomas. The protein expression of cdk6 and ckis viz. p16/Ink4A, p21/Waf1 and p27/Kip1 did not show any significant change in UVB exposed skin, but significant upregulation was observed both in papillomas and carcinomas. The results suggest that telomerase activation may be involved in UVB-induced tumorigenesis in mouse skin and that increased telomerase activity may be associated with G1 phase of the cell cycle.
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PMID:Activation of telomerase and its association with G1-phase of the cell cycle during UVB-induced skin tumorigenesis in SKH-1 hairless mouse. 1002 11

2-Acetylaminofluorene (AAF) is a potent tumor promoter in rat liver carcinogenesis models. In the resistant hepatocyte model, AAF is combined with a growth stimulus for efficient promotion of preneoplastic lesions. The promoting property of AAF in this model is closely associated with mito-inhibition of normal hepatocytes, an effect to which initiated cells are resistant. How AAF induces growth arrest is not known, but genotoxic as well as non-genotoxic effects have been implicated. To elucidate the mechanisms of AAF-induced mito-inhibition, we studied the expression of the tumor suppressor protein p53 and the cyclin-dependent kinase (cdk) complexes mediating G1 progression and S-phase entry. Hepatocytes were isolated from male Fisher 344 rats fed either a control diet or a diet supplemented with 0.02% AAF for 1 wk and cultured in a defined serum-free medium containing epidermal growth factor, insulin, and dexamethasone. Thymidine labeling revealed a profound inhibition of DNA synthesis in AAF-exposed cells compared with control cells. The retinoblastoma protein did not become hyperphosphorylated in AAF-exposed cells. Thus, inhibition of G1 cyclin-cdk activity was implied as a cause of growth arrest. Indeed, G1 cell-cycle arrest was accompanied by reduced induction and nuclear accumulation of the cyclin D1-cdk4 complex and inhibited nuclear translocation of cdk2. Furthermore, the growth arrest was not mediated through p21/waf1 upregulation, although nuclear levels of p53 were increased. Thus, carcinogen-induced mito-inhibition may be effected by altered levels and localization of G1 cyclin-cdk complexes, independent of the upregulation of cdk inhibitory proteins.
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PMID:Alteration of G1 cell-cycle protein expression and induction of p53 but not p21/waf1 by the DNA-modifying carcinogen 2-acetylaminofluorene in growth-stimulated hepatocytes in vitro. 1002 9

To study the altered mechanisms of cell cycle regulation in esophageal cancer, the expressions of cyclins involved in G1/S transition were analyzed in a series of 26 human esophageal cancer cell lines. To evaluate and compare the levels of cyclin expression, flow cytometric analysis was performed using human lymphocytes as control. Increased expressions of cyclin A, D1, D3 and E were found in 23.1% (6/26), 65.4% (17/26), 15.4% (4/26) and 57.7% (15/26) of the cell lines, respectively. All cell lines studied expressed less cyclin D2 than lymphocytes and the majority of the cell lines expressed cyclin D3 at levels similar to those of lymphocytes. Five cell lines expressed exceptionally high levels of cyclin E. Expressions of cyclin D1 and E were significantly elevated as compared to those of cyclin A, D2 and D3. These results suggest that increased expressions of the positive cell cycle regulators cyclin D1 and E may play an important role in esophageal carcinogenesis.
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PMID:Quantitative analysis of the cyclin expression in human esophageal cancer cell lines. 1008 73

The restriction of energy intake has a profound inhibitory effect on carcinogenesis, yet the mechanism or mechanisms that account for this effect are unknown. In this experiment, the hypothesis tested was that energy restriction upregulates the expression of p27/kip1, a gene product associated with cell-cycle growth arrest, while downregulating cyclin D1, a protein that combines with cyclin-dependent kinases to promote phosphorylation of retinoblastoma protein and the progression of cells through the cell cycle. We studied levels of these proteins in uninvolved mammary epithelial cells and in mammary intraductal proliferations, ductal carcinomas in situ, and adenocarcinomas induced in response to administration of 1-methyl-1-nitrosourea in animals fed either ad libitum or 90%, 80%, or 60% of ad libitum intake. Protein levels were evaluated immunohistochemically by using computer-assisted image analysis to quantify differences in protein expression among treatment groups. The expression of p27 increased and the expression of cyclin D1 decreased dose-dependently in response to energy restriction. The effect was greater on p27 than on cyclin D1. The hypothesis proposed is that energy restriction inhibits carcinogenesis by arresting cell-cycle progression by regulating p27/kip1.
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PMID:Effect of energy restriction on the expression of cyclin D1 and p27 during premalignant and malignant stages of chemically induced mammary carcinogenesis. 1032 60

Evidence has been recently provided on the relevant role of genomic imprinting in the regulation of implantation, embryonic development, placental growth, and also in development of proliferative trophoblastic diseases and human carcinogenesis. Among the various imprinted genes the cyclin-dependent-kinase inhibitor p57KIP2 (maternally imprinted) is particularly interesting since it can function as a tumor suppressor gene. In this review we describe the different roles of genomic imprinting in human diseases, with particular emphasis on the role of p57KIP2 in molar pregnancy and in tumorigenesis.
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PMID:Genomic imprinting in human biology and pathology. 1035 30

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
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PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66

The cyclin-dependent kinase (CDK) inhibitor p27(KIP1) exerts its growth suppressive effects by targeting the cyclin-CDK complexes. Reduced protein levels of p27(KIP1) have been reported in numerous human cancers and this has been attributed to increased degradation. However, few reports have addressed the significance of p27(KIP1) expression in chemical carcinogenesis of rodents. In a rat two-stage urinary bladder carcinogenesis model, with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) initiation followed by promotion with sodium L-ascorbate (Na-AsA), we evaluated the expression of p27(KIP1) protein using immunohistochemistry during various stages of urinary bladder carcinogenesis. In addition, we evaluated the mRNA expression profiles for p27(KIP1), p21(WAF1/Cip1) and p53 in tumors. Fisher 344 rats were initiated with 0.05% BBN in the drinking water for 4 weeks and then administered 5% Na-AsA in the diet. Immunohistochemical examination revealed p27(KIP1) protein to be constitutively expressed in normal urothelium, simple hyperplasia and in most papillary and nodular (PN) hyperplasias and small papillomas, but diminished or absent in large papillomas and in transitional cell carcinomas. An inverse correlation between expression of p27(KIP1) and cell proliferation was generally observed. Quantitation of mRNA by multiplex reverse transcription-PCR showed a significant downregulaton of p27(KIP1), p21(WAF1/Cip1) and p53 mRNA in tumors. More than 50% reduction in p27(KIP1) mRNA expression was observed in 42 and 47% of tumors at weeks 18 and 24, respectively; similar reduction in p21(WAF1/Cip1) mRNA expression was observed in 58 and 73% of tumors at weeks 18 and 24, and in p53 mRNA expression in 50 and 73% of tumors at weeks 18 and 24, respectively. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis had p53 mutations. These data imply that abnormal down-regulation of p27(KIP1), p21(WAF1/Cip1) and/or p53 in tumor cells may contribute to the malignant progression of tumors during rat two-stage bladder carcinogenesis.
Carcinogenesis 1999 Sep
PMID:Reduced expression of the CDK inhibitor p27(KIP1) in rat two-stage bladder carcinogenesis and its association with expression profiles of p21(WAF1/Cip1) and p53. 1046 13

Cyclin-dependent kinase (cdk) inhibitors, such as p16(INK4a) and p21(WAF1/CIP1), often inhibit G(1) cyclin kinases and result in G(1) arrest. It has been suggested that p21(WAF1/CIP1) may also play a role in other chemopreventive activities such as DNA repair, slowdown of DNA replication and induction of cellular differentiation. In this report we demonstrate that the antioxidant N-acetylcysteine (NAC), a well-known chemopreventive agent, induces p16(INK4a) and p21(WAF1/CIP1) gene expression and prolongs cell-cycle transition through G(1) phase. A portion of the G(1) arrest by NAC is governed by p16(INK4a); it is independent of p53. NAC's usual mechanism of increasing intracellular glutathione level is not required for the G(1) arrest. An antioxidant whose action is limited to scavenging radicals, Trolox, does not induce G(1) arrest. Taken together, these results suggest a potential novel molecular basis for chemoprevention by NAC.
Carcinogenesis 1999 Sep
PMID:Induction of cyclin-dependent kinase inhibitors and G(1) prolongation by the chemopreventive agent N-acetylcysteine. 1046 36


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