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: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine phosphorylation status was investigated during mouse mammary tumor development using non-tumorigenic and tumorigenic hyperplastic outgrowth lines. These outgrowth lines were compared with normal mammary glands from pregnant mice and with their corresponding tumors. The levels of total tyrosine phosphorylation in proteins of hyperplastic and neoplastic tissues were 4.7- and 3.4-fold higher than in the normal gland respectively. These results indicate that increases in tyrosine phosphorylation occur in the earliest stages of neoplastic development and are not restricted to neoplastic cells per se. These results led to the identification of the specific proteins showing high levels of tyrosine phosphorylation. Of the eight molecular weight bands of proteins exhibiting detectable levels of tyrosine phosphorylation, the only proteins exhibiting consistently different degrees of phosphorylation between hyperplasias and tumors were of approximately 34 kDa. In a series of six different hyperplasias with tumorigenic potentials ranging from 0 to 93%, the extent of tyrosine phosphorylation of 34 kDa proteins correlated inversely with tumorigenic potential. The levels of p34cdc2 and p33cdk2 proteins were examined, using antibodies specific for the cdc2 and cdk2 proteins. The amounts of p34cdc2 and p33cdk2 proteins were low in non-tumorigenic (TM3 and TM2L) compared to tumorigenic hyperplasias and correlated inversely with tyrosine phosphorylation of 34 kDa proteins during tumor development. Thus in the non-tumorigenic hyperplasias (TM2L and TM3) the majority of p34cdc2 was phosphorylated on tyrosine, in contrast to the p34cdc2 in tumorigenic (TM2H) hyperplasias and tumors. Two-dimensional PAGE analysis of mammary tumor samples with antibodies specific to cdc2, cdk2 and phosphorylated tyrosine revealed one p34cdc2 form, two p33cdk2 isoforms and two phosphotyrosine isoforms of about 33-34 kDa. The results suggest that the high levels of tyrosine phosphorylation in cdc2 and cdk2 reflect the low tumorigenic potential of a subset of mammary preneoplastic hyperplasias. This interpretation is in accord with current concepts on the role of tyrosine phosphorylation in the regulation of the cyclin-dependent kinases.
Carcinogenesis 1995 Apr
PMID:Tyrosine phosphorylation in mouse mammary hyperplasias. 772 75

It has recently become clear that cyclin-dependent kinase (cdk) complex regulates the cell cycle by phosphorylating Rb protein, a tumor suppressor protein. It is likely that this complex is a target of various growth factors and anti-growth factors (UV, TGF-beta etc.) in keratinocyte (KC). It has also been suggested that abnormalities in the cell cycle regulating mechanism such as increased activity of cyclin-cdk due to mutation of p53, a tumor suppressor gene, and overexpression of cyclin D may be concerned with carcinogenesis of KC. Thus, recent studies indicate that the cyclin-cdk complex is a common target of proliferation and carcinogenesis in KC.
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PMID:Cell cycle regulators in the keratinocyte (cyclin-cdk). 775 27

The MTS1/CDK4I gene encodes a 16 kDa cyclin kinase inhibitor and maps to chromosome 9p21. Previous studies have suggested the presence of a major tumour suppressor gene at this locus which may be inactivated in head and neck squamous cell carcinoma (HNSCC). To determine the status of this gene in human primary and metastatic HNSCC, we examined the locus and its transcript for abnormalities by polymerase chain reaction (PCR). Out of 14 cell lines studied, four had lost only exon 1, one had lost only exon 2, three had lost both exons 1 and 2, and none of the remaining six lines expressed a normal p16 mRNA. These latter six cell lines expressed p16 transcripts that had suffered deletions ranging in size from 2-16 base pairs. In each case, deletions led to a change of reading frame. Furthermore, in two cases abnormalities in the MTS1/CDK4I gene were identical in cells derived from metastatic tumours as compared to cells derived independently from the corresponding primary tumour. The identical nature of mutations observed in primary tumours and metastases derived from the same patient provides strong evidence that inactivation of p16 function was an in vivo event.
Carcinogenesis 1994 Dec
PMID:MTS1/CDK4I is altered in cell lines derived from primary and metastatic oral squamous cell carcinoma. 800 Dec 21

The progression of the cell cycle is controlled by the action of both positive and negative growth regulators. The key players in this activity include a family of cyclins and cyclin-dependent kinases, which are themselves regulated by other kinases and phosphatases. Maintenance of balanced cell cycle controls may be directly linked to genomic stability. Loss of the check-points involved in cell cycle control may result in unrepaired DNA damage during DNA synthesis or mitosis leading to genetic mutations and contributing to carcinogenesis.
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PMID:Cell cycle controls: potential targets for chemical carcinogens? 801 30

Gene amplification in stomach and oesophageal cancers was reviewed. In stomach cancers, two receptor type tyrosine kinases, c-erbB-2 and K-sam, are frequently amplified and overexpressed. c-erbB-2 seems to be preferentially amplified in well-differentiated, and K-sam in poorly-differentiated, gastric adenocarcinomas. 11q13 genes are amplified in about 50% of the oesophageal cancers. These genes include hst-1, int-2 and cyclin D/prad1, all of which are mapped to chromosome 11 at band q13. Although hst-1 and int-2 are usually not expressed despite amplification, elevated transcription of the cyclin D gene is accompanied by its amplification, suggesting a role of a G1 cyclin in oesophageal carcinogenesis.
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PMID:Amplified genes in cancer in upper digestive tract. 809 12

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

Recent studies have provided evidence suggesting that disruption of cyclin function may play a critical role in tumorigenesis. Cyclin D1, a putative G1 cyclin previously isolated in human parathyroid adenomas (designated PRAD1) and mouse macrophages (designated Cyl1), has been implicated in various neoplasias including breast and squamous cell carcinomas (SCC). The role of cyclin altered regulation in the different stages of tumor progression has not been studied in a well defined animal model system. In the study presented here, Cyl1 was mapped to the distal end of mouse chromosome 7 and found to be dramatically overexpressed in skin SCC. In premalignant stages of tumor development, early papillomas showed basal Cyl1 transcript levels, whereas over-expression was observed in most advanced papillomas. These findings suggest that altered expression of cyclin D1 plays a critical role in mouse skin carcinogenesis and may be related to the acquisition of autonomous growth by papillomas. Further studies on the role of cyclin D1 in the mouse model system should prove valuable for understanding the multistep basis of tumor progression.
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PMID:Overexpression of cyclin D1 in mouse skin carcinogenesis. 847 37

Ca2+ and Ca(2+)-binding proteins are involved in running the cell cycle. Ca2+ spikes and signals from integrin-activated focal adhesion complexes and Ca2+ receptors on the cell surface along with cyclic AMP begin the cycle of cyclin-dependent protein kinases (PKs). These transiently expressed PKs stimulate the coordinate expression of DNA-replicating enzymes, activate replication enzymes, inactivate replication suppressors (e.g., retinoblastoma susceptibility protein), activate the replicator complexes at the end of the G1 build-up, and when replication is complete they and a Ca2+ spike trigger mitotic prophase. Another Ca2+ surge at the end of metaphase triggers the destruction of the prophase-stimulating PKs and starts anaphase. Ca2+ finally stimulates cytoplasmic division (cytokinesis). However, Ca2+ does more than this in epithelial cells, such as those lining the colon, and skin keratinocytes. These cells also need Ca2+, integrin signals, and only a small amount (e.g., 0.05-0.1 mM) of external Ca2+ to start DNA replication. Signals from their surface Ca2+ receptors trigger a combination of differentiation and apoptosis ("diffpoptosis") when external Ca2+ concentration reaches their setpoints. The skin's steep, upwardly directed, Ca2+ gradient has a low concentration in the basal layer to allow stem and precursor keratinocytes to proliferate, and higher concentrations in the suprabasal layers to trigger the differentiation-apoptosis ("diffpoptosis") mechanism that converts granular cells into protective, hard-shelled, dead corneocytes. A similar Ca2+ gradient may exist in the colon crypt allowing the stem cell and its amplifying transit or precursor offspring to cycle in the lower parts of the crypt, while stopping proliferation and stimulating terminal differentiation in the upper crypt and flat mucosa. Raising the amount of Ca2+ in fecal water above a critical level reduces proliferation and thus colorectal carcinogenesis in normal rats and some high-risk humans. But during carcinogenesis the Ca2+ sensors malfunction or their signals become ineffective: high Ca2+ does not stop, and may even stimulate, the proliferation of initiated mutants. Therefore, Ca2+ may either not affect, or even promote, the growth of epithelial cells in carcinogen-initiated rat colon and human adenoma patients. Clearly, a much greater understanding of how Ca2+ controls the proliferation and differentiation of epithelial cells and why initiated cells lose their responsiveness to Ca2+ are needed to assess the drawbacks and advantages of using Ca2+ as a chemopreventor.
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PMID:Calcium-cell cycle regulator, differentiator, killer, chemopreventor, and maybe, tumor promoter. 853 13

The p15(INK4B), p16(INK4) and p18 genes are members of the gene family coding for inhibitors of cyclin-dependent kinases 4 and 6. p15(INK4B) and p16(INK4) are located at 9p21, a chromosomal region frequently deleted in many human neoplasms. To examine the role of these 3 genes in lung carcinogenesis, somatic mutations within the genes were analyzed by single-strand conformation polymorphism and DNA sequencing in 71 non-small-cell lung cancer (NSCLC) samples. Six somatic mutations in the p16(INK4) gene and 3 cases with a polymorphic allele were observed. Loss of heterozygosity in the p18 gene was found in 1 sample. We did not find any intragenic mutations in the p15(INK4B) or p18 genes. We conclude that p16(INK4) mutations play a role in the formation of some NSCLCs, whereas the involvement of p15(INK4B) and p18 is uncommon.
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PMID:Intragenic mutations of the p16(INK4), p15(INK4B) and p18 genes in primary non-small-cell lung cancers. 863 83

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


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