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

The tumor suppressor protein, p53, is proposed to have a critical role in maintaining the integrity of the genetic material. It has been established that p53 induces a cell cycle block in the G1 phase upon cellular DNA damage. Recent evidence also indicates the involvement of p53 directly and indirectly in nucleotide excision repair (NER). We have examined the role of p53 with respect to UV-induced mutagenesis. By gene transfer, we established a mouse fibroblast cell line overexpressing the val135 temperature-sensitive p53 allele. In this line, p53 activity can be modulated through temperature shift, as confirmed by Western blot and by cell cycle analysis. This cell line was also constructed to contain a recoverable lambda phage shuttle vector carrying the supF mutation reporter gene. Induction of p53 was found to enhance the clonogenic survival of the cells following UV-irradiation compared to the p53-deficient parental mouse cell line. The transfectant line also displayed a 4-fold reduction in the frequency of UV-induced mutations as measured in the chromosomally integrated supF reporter gene. Our results are consistent with a p53-induced cell cycle block at G1 allowing cells to repair chromosomal damage before DNA replication. However, our data may also reflect a more direct role of p53 in the repair of UV-induced lesions as suggested by studies showing that p53 can interact directly with repair factors.
Carcinogenesis 1995 Oct
PMID:Induction of p53 in mouse cells decreases mutagenesis by UV radiation. 758 25

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

A protein first identified by its association with cadherin cell adhesion molecules, beta-catenin, has been implicated in carcinogenesis. In a number of different types of cancer, signalling through beta-catenin is upregulated either by direct mutation of beta-catenin or loss of negative regulation by the APC tumor suppressor protein.
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PMID:Carcinogenesis: a balance between beta-catenin and APC. 921 Mar 68

High-risk human papillomavirus type 16 (HPV-16) and HPV-18 are associated with the majority of human cervical carcinomas, and two viral genes, HPV E6 and E7, are commonly found to be expressed in these cancers. The presence of HPV-16 E7 is sufficient to induce epidermal hyperplasia and epithelial tumors in transgenic mice. In this study, we have performed experiments in transgenic mice to determine which domains of E7 contribute to these in vivo properties. The human keratin 14 promoter was used to direct expression of mutant E7 genes to stratified squamous epithelia in mice. The E7 mutants chosen had either an in-frame deletion in the conserved region 2 (CR2) domain, which is required for binding of the retinoblastoma tumor suppressor protein (pRb) and pRb-like proteins, or an in-frame deletion in the E7 CR1 domain. The CR1 domain contributes to cellular transformation at a level other than pRb binding. Four lines of animals transgenic for an HPV-16 E7 harboring a CR1 deletion and five lines harboring a CR2 deletion were generated and were observed for overt and histological phenotypes. A detailed time course analysis was performed to monitor acute effects of wild-type versus mutant E7 on the epidermis, a site of high-level expression. In the transgenic mice with the wild-type E7 gene, age-dependent expression of HPV-16 E7 correlated with the severity of epidermal hyperplasia. Similar age-dependent patterns of expression of the mutant E7 genes failed to result in any phenotypes. In addition, the transgenic mice with a mutant E7 gene did not develop tumors. These experiments indicate that binding and inactivation of pRb and pRb-like proteins through the CR2 domain of E7 are necessary for induction of epidermal hyperplasia and carcinogenesis in mouse skin and also suggest a role for the CR1 domain in the induction of these phenotypes through as-yet-uncharacterized mechanisms.
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PMID:Both conserved region 1 (CR1) and CR2 of the human papillomavirus type 16 E7 oncogene are required for induction of epidermal hyperplasia and tumor formation in transgenic mice. 922 80

The mouse double minute 2 (mdm2) proto-oncogene was originally discovered as one of three genes that was amplified in a tumorigenic cell line derived from non-transformed Balb/c cells. Consistent with the expression pattern of mdm2 in these cells, it was later shown that the transforming potential of the mdm2 proto-oncogene can be activated by experimental overexpression. Overexpression of mdm2 protein been detected in a number of diverse human malignancies, indicating that this oncogene plays a key role in human carcinogenesis. One mechanism by which mdm2 overexpression may lead to uncontrolled cellular proliferation is through its ability to physically associate with the p53 tumor suppressor and block p53's growth suppressive functions. Forced overexpression of mdm2 has been shown to block the transactivation, cell cycle arrest and apoptotic functions of p53. The mdm2 gene has also been shown to be a transcriptional target of p53 and the induction of p53 transcriptional activity leads to increases in mdm2 RNA and protein levels. Thus, it appears that an auto-regulatory feedback loop exists between these two proteins which keeps the growth suppressive functions of p53 in check during normal cell cycling. However, this block is thought to be overcome during certain cellular insults, including DNA damage, so that p53 can regulate the expression of genes involved in cell cycle arrest and/or apoptosis. Genetic lesions leading to elevated levels of mdm2 likely impair the ability of p53 to orchestrate the expression of genes controlling cell cycle progression during cellular insults. This may lead to the propagation of genetic errors, genomic instability and ultimately to an increase in the rate of tumor cell evolution. There is also recent evidence which suggests that mdm2 may play roles in p53-independent pathways regulating cellular proliferation. mdm2 has recently been shown to interact with the retinoblastoma tumor suppressor protein p(Rb), and the E2F-1 and DP1 transcription factors. These, and other clinical, cellular and biochemical studies relating to the mdm2 oncogene are reviewed here. In addition, a proposed role for mdm2 in pathways controlling cell cycle response to cellular perturbations is presented.
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PMID:The mdm2 proto-oncogene. 932 85

In the majority of cervical cancers, DNAs of high-risk mucosotpropic human papillomaviruses (HPVs), such as type 16, are maintained so as to express two viral proteins, E6 and E7, suggesting an essential importance to carcinogenesis. The high-risk HPV E6 proteins are known to inactivate p53 tumor suppressor protein but appear to have an additional, molecularly unknown function(s). In this study, we demonstrate that these E6 proteins can bind to the second PDZ domain of the human homologue of the Drosophila discs large tumor suppressor protein (hDLG) through their C-terminal XS/TXV/L (where X represents any amino acid, S/T serine or threonine, and V/L valine or leucine) motif. This finding is similar to the interaction between the adenomatous polyposis coli gene product and hDLG. E6 mutants losing the ability to bind to hDLG are no longer able to induce E6-dependent transformation of rodent cells. These results suggest an intriguing possibility that interaction between the E6 protein and hDLG or other PDZ domain-containing proteins could be an underlying mechanism in the development of HPV-associated cancers.
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PMID:Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. 932 58

Molecular markers such as mutational spectra or mRNA expression patterns may give some indication of the mechanisms of carcinogenesis induced by fibers and other carcinogens. In our study, tumors were induced by application of crocidolite asbestos or benzo[a]pyrene (B[a]P) to rat peritoneum. DNA and RNA of these tumors were subjected to analysis of point mutations and to investigation of mRNA expression patterns. With both assays we found typical features depending on the type of carcinogen applied. The analysis of point mutations in the tumor suppressor gene p53 revealed mutations in the B[a]P-induced tumors. However, in the tumors induced by crocidolite asbestos that were of the same tumor type as those induced by B[a]P, mutations in p53 were not detectable. Every mutation detected on the DNA level causes an amino acid substitution within one of the functional domains of the tumor suppressor protein. Therefore, these mutations seem to be of biological relevance for tumor progression and indicate a difference in the carcinogenesis regarding the type of the carcinogenic substance. An additional specificity of crocidolite-induced tumors was detectable by analyzing the mRNA expression of the tumor suppressor gene WT1, which is known to be expressed in human mesothelial and mesothelioma cells. A relatively high amount of WT1 mRNA was measured by quantitative competitive reverse transcription-polymerase using RNA extracted from crocidolite-induced tumors. However, WT1 seems to be expressed on a rather low level in tumors induced by B[a]P.
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PMID:Fiber-specific molecular features of tumors induced in rat peritoneum. 940 Jul 7

The p16/MTS1 gene is altered by deletion, mutation, or hypermethylation in a wide variety of human cancers. As a result of deficient p16 protein, these cancers lack a critical mechanism for halting G1/S cell cycle progression. In the current study, 59 cases of nasopharyngeal carcinoma were evaluated for expression of the p16 tumor suppressor protein by immunohistochemical analysis of paraffin-embedded tissue. There was no detectable p16 in 38/59 cases (64%), which implies a very high rate of p16 inactivation in this type of cancer. On the other hand, the retinoblastoma gene product, which also regulates the G1 to S phase transition of the cell cycle, was consistently expressed in nasopharyngeal carcinomas by immunohistochemical analysis. These results implicate p16 inactivation but not Rb alteration in the stepwise progression of nasopharyngeal carcinogenesis.
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PMID:Nasopharyngeal carcinomas frequently lack the p16/MTS1 tumor suppressor protein but consistently express the retinoblastoma gene product. 954 45

The NF1 gene product (neurofibromin) is known to act as a tumor suppressor protein by inactivating ras. The best documented factors involved in urinary bladder transitional cell carcinoma (TCC) are ras proto-oncogene activation and p53 suppressor gene mutations. This is the first study reporting alterations in NF1 gene expression in TCC. We examined NF1 gene expression in a total of 29 surgical urinary bladder TCC specimens representing grades 1 to 3 and in three cell lines, RT4, 5637, and T24 (representing grades 1 to 3, respectively). Decreased NF1 gene expression was observed in 23 of 29 (83%) TCC specimens as estimated by immunohistochemistry, the decrease being more pronounced in high-grade tumors. NF1 mRNA levels were markedly lower in TCC tissue compared with adjacent non-neoplastic urothelium, as studied by in situ hybridization for grade 3 TCC. Immunohistochemistry and Western blotting demonstrated that TCC cell lines expressed NF1 protein at different levels, expression being almost undetectable in T24 (grade 3) cells. Northern blotting for cell lines demonstrated reduced NF1 mRNA levels in grade 3 TCC cells. Reverse transcription polymerase chain reaction for cell lines and selected grade 2 and grade 3 tissue samples demonstrated NF1 type II mRNA isoform predominance in all samples studied. Our results show that both NF1 mRNA and protein levels are decreased in high-grade TCC, suggesting that alterations of NF1 gene expression may be involved in bladder TCC carcinogenesis.
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PMID:Urinary bladder transitional cell carcinogenesis is associated with down-regulation of NF1 tumor suppressor gene in vivo and in vitro. 1007 53

Studies presented here show that cellular NAD, which we hypothesize to be the relevant biomarker of niacin status, is significantly lower in humans than in the commonly studied animal models of carcinogenesis. We show that nicotinamide and the resulting cellular NAD concentration modulate expression of the tumor suppressor protein, p53, in human breast, skin, and lung cells. Studies to determine the optimal NAD concentrations for responding to DNA damage in breast epithelial cells reveal that DNA damage appears to stimulate NAD biosynthesis and that recovery from DNA damage occurs several hours earlier in the presence of higher NAD or in cells undergoing active NAD biosynthesis. Finally, analyses of normal human skin tissue from individuals diagnosed with actinic keratoses or squamous cell carcinomas show that NAD content of the skin is inversely correlated with the malignant phenotype. Since NAD is important in modulating ADP-ribose polymer metabolism, cyclic ADP-ribose synthesis, and stress response proteins, such as p53, following DNA damage, understanding how NAD metabolism is regulated in the human has important implications in developing both prevention and treatment strategies in carcinogenesis.
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PMID:Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. 1033 40


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