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)

Human papillomaviruses (HPVs) have been recognized as likely viral agents responsible for anogenital precancer lesions and squamous cell cancers in both men and women. Nevertheless their role in carcinogenesis is not entirely clear. There are many other agents, both viral and non-viral, which might act synergistically or separately with HPV in a multistep tumorigenic process. Among non-viral factors, protooncogene and tumor suppressor gene alterations may be a major step towards the malignant transformation of an HPV-infected cell. The induction of unscheduled DNA synthesis and cell proliferation by human papillomaviruses would provide the basis for the potential of these viruses to contribute to the formation of tumors in vivo. Thus, we studied by in situ hybridization (ISH) the cyclin A gene expression in HPV-induced condylomatous and dysplastic lesions of the anogenital tract, and in inflammatory squamous intraepithelial tissues. We observed a high level of cyclin A gene expression in low grade squamous intraepithelial lesions infected by HPV type 6/11. Cyclin A induction was surprisingly more important in the upper third layers of differentiated cells together with large amounts of HPV DNA, than in proliferating basal and parabasal cells. An identical pattern was also shown in some low grade squamous intraepithelial lesions infected with potential oncogenic HPV. In contrast, there was evidence of low abundance cyclin A mRNA in most high grade squamous intraepithelial lesions induced by high risk HPV. In the inflammatory tissues, an ISH signal was sometimes detected in the basal cells. As for proliferating cell nuclear antigen (PCNA), these results observed in vivo reveal that viral oncoproteins are able to reactivate cellular DNA replication machinery to support papillomavirus DNA replication in normally differentiated, non-cycling cells. The induction of cyclin A gene expression appears to correlate with the proliferative rather than the transforming properties of these cells.
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PMID:[Detection of cyclin A mRNA in intra-epithelial lesions of the anogenital tract induced by papillomavirus]. 764 62

Breast cancer in humans, as in mice and rats, is thought to be the result of sequential changes in the epithelial cells of the mammalian glands. This study examines the altered expression or activation of cell cycle related proteins in an in situ system composed of hyperplasia, preneoplasia and neoplasia of mouse mammary glands. The results showed a high level of cdc2/cdk2 kinase activities in tumors compared to hyperplasias which was independent of cdc2/cdk2 protein levels. Some of the cdk-associated proteins which are thought to regulate cdk kinase activity were examined in these tissues. Cyclin A was overexpressed in all hyperplasias irrespective of their tumorigenic potentials. However, a number of alterations in cyclin E protein were associated with cdk2 and its associated kinase activity during mammary tumorigenesis. First, the level of normal cyclin E (p50) expression was positively correlated with the tumorigenic potentials of different hyperplasia lines. Second, several cyclin E isoforms (p48, p43, p35, p34, p32) were detected only in tumor tissues. Third, a 2.3- and 8.3-fold increase in cyclin E-associated cdk2 kinase activity was present in highly tumorigenic hyperplasias and neoplasias respectively compared to the low tumorigenic hyperplasias. Polymorphic cell nuclear antigen (PCNA) protein bound to cdk2 was a better indicator for cell proliferation and cdk2 kinase activity than the PCNA labeling index. These results suggest a sequential pattern of multiple derangements in factors regulating cdk2 protein function during mammary tumorigenesis. High levels of cdk2 kinase activity are observed only in tumors and appear to be closely related to alterations in cyclin E protein expression.
Carcinogenesis 1995 Apr
PMID:Cell cyclins and cyclin-dependent kinase activities in mouse mammary tumor development. 772 62

Cyclin A associates with both the p34 cdc2 and p33 cdk2 kinases and is involved at two major check-points (G1-S and G2-M) of the cell cycle. The cyclin has been identified in multimeric protein complexes that incorporate the E2F transcription factor, the p33 cdk2 kinase, and p107, which is related to the retinoblastoma protein. Therefore, cyclin A provides a link between studies on the cell-cycle machinery and those aiming to elucidate the modulation of cell proliferation and regulation of gene expression by oncogenes and growth-suppressor proteins. The modification of cyclin A expression in a human liver cancer by the insertion of hepatitis B viral DNA into the cyclin A gene, and binding of cyclin A to the oncogenic E1A viral protein in adenovirus-infected cells suggest that the cyclin is implicated in human carcinogenesis. In addition, cyclin A might also be considered as a marker for tumor-cell proliferation in oncology. With these views in mind, it is now important to extend these observations to other types of cancer.
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PMID:Oncogenic activation of cyclin A. 838 33

The E6/E7 oncoproteins of human papillomavirus (HPV) types 16 and 18 are responsible for the efficient immortalization of human genital keratinocytes and we have recently reported that such immortalized cells display alterations in the expression of cyclin A, cyclin B, and cdc-2. To determine whether these alterations were the consequence of E6/E7 protein expression or whether they resulted from the process of cellular immortalization, we multiply-infected primary genital keratinocytes with a retrovirus expressing the HPV-18 E6/E7 genes and examined the cells for acute, pre-immortalization changes in several critical cell growth regulatory proteins including cyclin A, cyclin B, cdc-2, p53 and c-myc. In addition, we simultaneously evaluated the expression of the E6/E7, bcl-2 and involucrin genes to determine whether there were accompanying alterations in the expression of viral genes or in cellular genes related to cell apoptosis and the state of keratinocyte differentiation. The cell cycle regulating proteins (cyclin A, cyclin B, cdc-2 and p53) change significantly within days after retroviral infection. Cyclin B and cdc-2 increase over 4-fold by three passages and remain relatively constant thereafter through passage 21, whereas the levels of p53 protein decrease 25% by passage three. Increases in the expression of cyclin A, cyclin B and cdc-2, and decreases in p53 are therefore among the earliest observable changes in cell regulatory proteins following E6/E7 gene expression and may be important contributors to the development of cell immortalization. The expressions of viral E6/E7 genes, c-myc, bcl-2 and involucrin exhibit progressive changes with increased passage numbers until passage 21, presumably reflecting the selective outgrowth of immortalized cells.
Carcinogenesis 1996 Jul
PMID:The human papillomavirus E6/E7 genes induce discordant changes in the expression of cell growth regulatory proteins. 870 40

Cyclin A is a key regulatory protein which, in mammalian cells, is involved in both S phase and the G2/M transition of the cell cycle through its association with distinct cdks. Several lines of evidence have also implicated cyclin A in carcinogenesis. Our review concentrates on the role of cyclin A in S phase, in the S/G2 transition and in human carcinogenesis; it will also discuss the transcriptional regulation of cyclin A gene.
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PMID:Cyclin A: function and expression during cell proliferation. 955 57

Cyclins are important regulators of the cell cycle; there is increasing evidence that some cyclins are positively involved in carcinogenesis. Amplification and translocation of the cyclin genes and overexpression of their mRNAs and proteins have been observed in a variety of tumours. We studied cyclin A protein in astrocytic tumours by immunohistochemical analysis. Immunohistochemistry with microwave antigen retrieval was carried out on formalin fixed, paraffin embedded material from 15 glioblastomas (WHO grade IV), 10 anaplastic astrocytomas (WHO grade III), seven diffuse low grade astrocytomas (WHO grade II) and nine pilocytic astrocytomas (WHO grade I) using antibodies against cyclin A and a proliferation marker MIB1. Staining for these antibodies was seen mainly in the tumour cell nuclei; 66% of all cases showing staining for cyclin A and 95% of all cases staining for MIB1. Mean labelling indices (LI) for cyclin a were higher in glioblastoma (mean LI-6.7) and anaplastic astrocytoma (mean LI-5.9) than low grade diffuse astrocytoma (mean LI-1.7) and pilocytic astrocytoma (mean LI-0.12), although there was no clear cut off point between the various tumour types. A good correlation was seen between labelling indices of cyclin A and MIB1 (Pearson correlation coefficient r = 0.59, P < 0.0001). Cyclin A is variably expressed in astrocytic tumours, either reflecting increased tumour proliferation (cyclin A being an integral component of the cell cycle), an alteration of its gene, protein upregulation or regulation of apoptosis. The genetic basis of expression of cyclin A in astrocytic tumours remains to be determined.
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PMID:Immunohistochemical analysis of cyclin A in astrocytic tumours. 971 90

Fusarium moniliforme is a widespread fungal pathogen which primarily infects corn, but can also infect rice or wheat. Fusarium moniliforme produce several mycotoxins, the most prominent of which is called fumonisin B1 (FB1). Epidemiological studies have indicated that ingestion of fumonisins correlates with a higher incidence of oesophageal cancer in Africa and China. Fumonisins also cause a neurodegenerative disease in horses, induce hepatic cancer in rats, are nephrotoxic in rats, or cause pulmonary oedema in swine. Structurally, fumonisins resemble sphingolipids and can alter sphingolipid biosynthesis. suggesting that sphingolipid alterations play a role in disease and carcinogenesis. Previous studies determined that FB1 blocked cell-cycle progression in CV-1 cells but not COS-7 cells. Herein, we have examined the effects that FB1 treatment has on cell-cycle regulatory proteins. Our studies established that FB1 treatment of CV-1 cells, but not COS-7 cells, leads to dephosphorylation of the retinoblastoma (Rb) protein. Cyclin dependent kinase 2 (CDK2) activity was repressed five- to 10-fold and cyclin E protein levels were lower in CV-1 cells after fumonisin treatment. Two CDK inhibitors, Kip1 and Kip2, were induced within 3 hours after fumonisin treatment of CV-1 cells, suggesting these two proteins mediate cell-cycle arrest induced by FB1. This mycotoxin caused large increases in sphinganine within 3 hours after addition of FB1. As sphingoid bases are known to induce Rb phosphorylation, this increase in sphinganinie might be the stimulus for the suppression of cyclin dependent kinase activities via Kip1 and Kip2. The ability of FB1 to accumulate sphingosine or sphinganine and arrest the cell cycle in some cells but not others may play an important role in carcinogenesis or disease.
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PMID:Characterization of cell-cycle arrest by fumonisin B1 in CV-1 cells. 973 26

Several in vitro studies have shown that cyclin A gene alteration in the cell cycle plays an important role in carcinogenesis. We immunohistochemically examined the expression of cyclin A protein in 120 patients with transitional cell carcinoma (TCC) of the renal pelvis and ureter, including adjacent dysplastic lesions to determine their significance for the tumor behavior and patient prognosis. Cyclin A immunostaining of the nucleus was observed in 29 tumors (24.2%). Furthermore, 17 cyclin A-positive tumors (58.6%) had dysplastic lesions positive for cyclin A antibody. The prevalence of cases exhibiting cyclin A staining was higher in the high grade (P < 0.01) and invasive tumors (P < 0.05) than in the other types of tumors. In the selected 117 cases, patients whose TCCs expressed a high level of cyclin A protein had a significantly poorer prognosis than those without cyclin A expression (P < 0.01). These in vivo findings provide the first evidence for frequent and redundant cyclin A protein overexpression in TCC and suggest that cyclin A overexpression is related to the tumor behavior and patient prognosis. In addition, our observations indicate that overexpression of cyclin A may be one of the early events, at least in some cases, in the carcinogenesis of TCC.
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PMID:Cyclin A overexpression in carcinoma of the renal pelvis and ureter including dysplasia: immunohistochemical findings in relation to prognosis. 981 24

In order to investigate the hypothesis that aberrant expression of cell-cycle regulatory proteins may represent early events in the process of carcinogenesis, levels of expression of the negative regulators p21(waf1/cip1) (p21), p27(kip1) (p27), and p16(ink4a) (p16) and/or the positive regulators cyclin D(1) and cyclin E were examined by western blot analysis in cells transformed in vitro by ionizing radiation. The levels of these proteins in 12 independently derived mouse 10T(1/2) cell clones transformed by 1.5 Gy of alpha radiation were compared with those in nine similarly derived nontransformed control clones. Constitutive levels of p21 were very low in all control clones, whereas p21 expression was significantly elevated in nine of 12 transformed clones. Two of the three transformed clones displaying low levels of p21 expressed increased levels of p53. p21 regulation was also altered in response to radiation in transformed clones as compared with controls, only minimal induction was observed 4 h following gamma irradiation. Western blot analysis indicated a constant expression of p27 protein but slightly decreased levels of p16 in these transformed clones. Cyclin D(1) was overexpressed in 11 of 12 transformed clones; in only two of these were the levels of cyclin E elevated. Overall, the results suggest that alterations in the expression of cell cycle regulatory proteins may represent important events in radiation-induced oncogenic transformation in vitro. Although the specific alterations vary among different transformed clones, overexpression and aberrant regulation of p21 appear to be the most frequent ones.
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PMID:Overexpression of p21 protein in radiation-transformed mouse 10T(1/2) cell clones. 1065 6

The gene expression pattern of mesothelial cells in vitro was determined after 4 or 12 h exposure to the rat mesothelial, kidney, and thyroid carcinogen and oxidative stressor potassium bromate (KBrO(3)). Gene expression changes observed using cDNA arrays indicated oxidative stress, mitotic arrest, and apoptosis in treated immortalized rat peritoneal mesothelial cells. Increases occurred in oxidative stress responsive genes HO-1, QR, HSP70, GADD45, GADD153, p21(WAF1/CIP16), GST's, GAPDH, TPX, and GPX-1(0); transcriptional regulators c-jun, c-fos, jun B, c-myc, and IkappaB; protein repair components Rdelta, RC10-II, C3, RC-7, HR6B ubiquitin-conjugating enzyme and ubiquitin; DNA repair components PCNA, msh2, and O-6 methylguanine DNA methyltransferase; lipid peroxide excision enzyme PLA2; and apoptogenic components TNFalpha, iNOS1 and FasL. Decreases occurred in bcl-2 (antiapoptotic), bax alpha, bad, and bok (proapoptotic) and cell cycle control elements (cyclins). Cyclin G and p14ink4b (which inhibit entry into cell cycle) were increased. Numerous signal transduction, cell membrane transport, membrane-associated receptor, and fatty acid biosynthesis and repair components were altered. Morphologic endpoints examined were number of mitotic figures, number of apoptotic cells, and antibody-specific localization of HO-1 (which demonstrated increased HO-1 protein expression). PCR analysis confirmed HO-1, p21(waf1/cip1), HSP70, GPX1, GADD45, QR, mdr1, PGHS, and cyclin D1 changes. A model for KBrO(3)-induced carcinogenicity in the F344 rat mesothelium is proposed, whereby KBrO(3) generates a redox signal that activates p53 and results in transcriptional activation of oxidative stress and repair genes, dysregulation of growth control, and imperfect DNA repair leading to carcinogenesis.
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PMID:Morphologic analysis correlates with gene expression changes in cultured F344 rat mesothelial cells. 1113 43


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