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)

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

We initiated studies to investigate the involvement of the murine retinoblastoma (RB) gene in mammary carcinogenesis using cell lines derived from mammary glands of irradiated mice. We found that the RB mRNA levels as well as the amounts of the nuclear phosphoprotein were significantly reduced as the cells progressed in vitro from non-tumorigenic to tumorigenic stages. To further investigate RB gene expression with cellular development and tumorigenicity, we transfected malignant cells with expression vectors containing the murine RB cDNA driven by either the SV40 or the mouse metallothionein promoter sequences. The neomycin resistant gene was included in both vectors and was used as a selective marker for the transfected cells. Cells with reduced levels of endogenous RB mRNA were stably transfected and showed increased expression of RB. In addition, the morphology of these cells were altered and their growth rates in culture were reduced. Injection of the transfected cells into host mice resulted in a delayed onset of tumors compared with nontransfected parental cells. Our studies provide experimental data to confirm that loss of RB gene activity is involved in neoplastic transformation of cells and support the multistep theory of carcinogenesis.
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PMID:Regulation of retinoblastoma gene expression in a mouse mammary tumor model. 854 79

Abnormality of the molecules regulating the cell cycle has been shown to lead cells to transformation. Recently, overexpression of cyclin D protein, one of the G1 cyclins, and the abnormality of the retinoblastoma gene have been found in various human cancers. We analyzed the expression of cyclin D, retinoblastoma gene product (pRB) and p53 in actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) by immunohistochemistry to elucidate the role of these molecules in keratinocyte carcinogenesis. In the normal epidermis, a few cyclin D positive cells were seen mainly at the basal layer. In 11 seborrheic keratoses, no overexpression of cyclin D was observed. Twelve of 26 AKs (46%) and 27 of 45 SCCs (60%) showed cyclin D overexpression. A few pRB positive cells were seen in the basal layer and in the suprabasal spinous layer of the normal epidermis. An abnormality of pRB, loss of expression, was seen in 2 of 26 AKs (8%) and 7 of 45 SCCs (16%). p53 protein was positive in 12 of 26 AKs (46%) and 24 of 45 SCCs (53%). Forty-five SCCs examined were divided into 22 ultraviolet (UV)-related SCCs and 23 UV-unrelated SCCs. Though UV-related SCCs showed a significantly higher incidence of p53 positivity, as previously reported by us, no significant difference in cyclin D overexpression and loss of the pRB expression was observed between UV-related and UV-unrelated SCCs. These results suggest that cyclin D overexpression is frequently involved in keratinocyte carcinogenesis and that this is an early event, as well as p53 abnormality. In addition, abnormality of the retinoblastoma gene is also related to epidermal cell carcinogenesis, though the frequency is relatively low.
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PMID:Cyclin D and retinoblastoma gene product expression in actinic keratosis and cutaneous squamous cell carcinoma in relation to p53 expression. 859 75

According to a "two-hit" model, dominantly inherited predisposition to cancer entails a germline mutation, while tumorigenesis requires a second, somatic, mutation. Non-hereditary cancer of the same type requires the same two hits, but both are somatic. The original tumor used in this model, retinoblastoma, involves mutation or loss of both are somatic. The original tumor used in this model, retinoblastoma, involves mutation or loss of both copies of the RB1 tumor-suppressor gene in both hereditary and non-hereditary forms. In fact, most dominantly inherited cancers show this relationship. New dominantly inherited cancers show this relationship. New questions have arisen, however. When a tumor-suppressor gene is ubiquitously expressed, why is there any specificity of tumor predilection? In some instances, it is clear that two hits produce only a benign precursor lesion and that other genetic events are necessary. As the number of necessary events increase, the impact of the germline mutation diminishes. The number of events is least for embryonal tumors, and relatively small for certain sarcomas. Stem-cell proliferation evidently plays a key role early in carcinogenesis. In some tissues it is physiological, as in embryonic development and in certain tissues in adolescence. In adult renewal tissues, the sites of the common carcinomas, mutation may be necessary to impair the control of switching between renewal and replicative cell divisions; the APC gene may be the target of such a mutation.
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PMID:Hereditary cancer: two hits revisited. 860 60

The human papillomavirus type 16 (HPV-16) genome is commonly present in human cervical carcinoma, in which a subset of the viral genes, E6 and E7, are expressed. The HPV-16 E6 and E7 gene products can associated with and inactivate the tumor suppressor proteins p53 and Rb (the retinoblastoma susceptibility gene product), and in tissue culture cells, these viral genes display oncogenic properties. These findings have led to the hypothesis that E6 and E7 contribute to cervical carcinogenesis. This hypothesis has recently been tested by using transgenic mice as an animal model. HPV-16 E6 and E7 together were found to induce cancers in multiple tissues in which they were expressed, including squamous cell carcinoma, the cancer type most commonly associated with HPV-16 in the human cervix. We have extended these studies to investigate the in vivo activities of HPV-16 E7 when expressed in squamous epithelia of transgenic mice. Grossly, E7 transgenic mice had multiple phenotypes, including wrinkled skin that was apparent prior to the appearance of hair on neonates, thickened ears, and loss of hair in adults. In lines of mice expressing higher levels of E7, we observed stunted growth and mortality at an early age, potentially caused by an incapacity to feed. Histological analysis demonstrated that E7 causes epidermal hyperplasia in multiple transgenic lineages with high penetrance. This epithelial hyperplasia was characterized by an expansion of the proliferating compartment and an expansion of the keratin 10-positive layer of cells and was associated with hyperkeratosis. Hyperplasia was found at multiple sites in the animals in addition to the skin, including the mouth palate, esophagus, forestomach, and exocervix. In multiple transgenic lineages, adult animals developed skin tumors late in life with low penetrance. These tumors arose from the squamous epithelia and from sebaceous glands and were characterized histologically to be highly differentiated, locally invasive, and aggressive in their growth properties. On the basis of these phenotypes, we conclude that HPV-16 E7 can alter epithelial cell growth parameters sufficiently to potentiate tumorigenesis in mice.
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PMID:Squamous epithelial hyperplasia and carcinoma in mice transgenic for the human papillomavirus type 16 E7 oncogene. 862 12

Abnormalities in the Retinoblastoma tumor suppressor gene (Rb) have been observed in a large number of human cancers. Loss of heterozygosity (LOH) is a common mode of allelic inactivation of Rb and other tumor suppressor genes. We investigated DNA from 45 primary human head and neck cancers to determine LOH at the Rb locus using a polymerase chain reaction-based restriction fragment length polymorphism assay. Of informative cases, we found LOH in 4 of 28 (14%) head and neck cancers. Of immunohistochemical staining of Rb protein, we found that in one of ten LOH negative cases the nuclei of fibroblasts were stained with anti-Rb antibody but there was no nuclear staining tumor cells. These results suggest that inactivation of Rb protein is involved in the carcinogenesis of head and neck cancer at all levels of the process of protein expression: DNA, mRNA and protein.
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PMID:Abnormalities and the implication of retinoblastoma locus and its protein product in head and neck cancers. 868 9

Abnormalities in the p53 tumor suppressor gene have been shown to affect cellular processes related to cell cycle control and gene amplification. In this study we compare the status and function of wild-type p53 in MCF-7 breast cancer cells with sublines selected for resistance to chemotherapeutic agents having different mechanisms of action. Sublines that were resistant to melphalan, pyrazafurin, mitoxantrone, etoposide and PALA all retained expression of wild-type p53. Methotrexate-resistant MCF-7 cells were unusual heterozygotes that expressed a wild-type and dominant, in-frame p53 deletion mutant and the doxorubicin-resistant cells expressed only mutant p53. Analysis of the G1 checkpoint after treatment with ionizing radiation revealed that the pyrazafurin-, melphalan- and mitoxantrone-resistant cells arrested strongly in G1. The etoposide- and PALA-resistant cells had an intermediate G1 arrest phenotype and the methotrexate- and doxorubicin-resistant cells had a minimal G1 arrest phenotype. mRNA and protein analyses of downstream effector genes, including P21CIP1/Waf1, mdm2, Gadd 45 and the retinoblastoma protein, did not entirely differentiate sublines having a strong versus intermediate G1 arrest phenotype. Neither the p53 status nor the strength of the G1 arrest could be correlated with cell survival after ionizing radiation. When drug-sensitive MCF-7 cells were treated with the same chemotherapeutic agents, p53 and p21CIP1/Waf1 levels increased between 2- and 14-fold. Together these data suggest that other cellular factors likely play a role in overcoming the inhibitory effects of ionizing radiation on p53 in drug-resistant breast cancer cells.
Carcinogenesis 1996 Jul
PMID:Drug-resistant breast cancer cells frequently retain expression of a functional wild-type p53 protein. 870 43

To better understand the cell lineage-specific character of retinoblastoma (Rb) gene inactivation during tumor formation, the earliest stages of spontaneous melanotroph carcinogenesis in Rb+/- heterozygous mice have been subjected to sequential analyses. The first atypical cells are detected in the pituitary intermediate lobe during a period corresponding to the cessation of melanotroph proliferation between 35 and 60 days after birth. Atypical cells contain no wild-type copy of the Rb gene and synchronously form early atypical proliferates (EAP) in the subsequent 30-60 day period. In contrast to surrounding mature melanotrophs with the wild-type Rb gene, Rb-negative cells in EAP continue to proliferate well past postnatal day 60, and fail to be innervated by growth inhibitory dopaminergic nerve terminals. Atypical melanotrophs remain competent for dopamine D2 receptor stimulation and undergo S-phase apoptosis in close proximity to nerve terminals. These results indicate a key role for the Rb protein in the onset of neuron-neuroendocrine cell interactions. This role may explain cell-type-specific neuroendocrine carcinogenesis associated with inactivation of the ubiquitously expressed Rb gene.
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PMID:Early loss of the retinoblastoma gene is associated with impaired growth inhibitory innervation during melanotroph carcinogenesis in Rb+/- mice. 875 45

The occurrence of retinoblastoma gene abnormalities in a large subset of various malignancies suggests an important role for this tumour suppressor gene in carcinogenesis, but this varies considerably from one tumour type to another and results in patients with acute myeloid leukaemia (AML) have been controversial. We analysed 106 AML patients and 18 normal controls for RB1 gene rearrangements and 86 AML patients for RB protein (pRB) expression. Southern blot analysis detected no gross gene rearrangements, but several restriction enzyme polymorphisms were observed. By Western blot analysis, 20 patients (23%) had no detectable pRB protein and seven (8%) had truncated pRB bands. Discordance between the DNA and protein data suggests that there may be minor deletions and point mutations in the RB1 gene or abnormalities in the proteins regulating the expression of pRB. No significant differences in the frequency of attainment of complete remission or length of survival were observed between patients with normal and abnormal pRB.
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PMID:The retinoblastoma gene (rb1) in acute myeloid leukaemia: analysis of gene rearrangements, protein expression and comparison of disease outcome. 875 95

There have been many new developments in our understanding of esophageal carcinoma biology over the past several years. Information regarding both of the major forms of this disease, adenocarcinoma and squamous cell carcinoma, has accumulated in conjunction with data on precursor conditions such as Barrett's esophagus. Some of the most interesting and promising findings have included aneuploidy (abnormal DNA content), amplification and overexpression of proto-oncogenes, loss of heterozygosity at multiple chromosomal loci, and tumor suppressor gene inactivation. Of particular importance is mutation and deletion involving the tumor suppressor gene p53, but abnormalities in the retinoblastoma, deleted in colon cancer, and adenomatous polyposis coli genes have been described as well. Recently, two important cancer pathways implicated in the genesis of multiple tumor types have also been inculpated in esophageal carcinogenesis: the cyclin kinase inhibitor cascade and the DNA mismatch repair process. Alterations in the p16 and p15 cyclin kinase inhibitors, including point mutation and homozygous deletion, have been reported in primary esophageal tumors and/or tumor-derived cell lines. Microsatellite instability, the hallmark of DNA mismatch repair defects, has been detected in esophageal cancers, particularly those associated with Barrett's metaplasia (where it may represent an early event). Further developments in the field of molecular carcinogenesis of esophageal malignancies promise to yield improvements in the early detection, prognostic categorization, and perhaps eventual gene-based therapy of this deadly disease.
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PMID:The molecular biology of esophageal carcinoma. 889 31


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