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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.
Mol Cell Biol 1992 Mar
PMID:Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. 134 43

From a liver metastasis of a human pancreatic adenocarcinoma, we have established cell lines for studying the cell biology of this tumor. We obtained two cell lines with different morphological, chromosomal and functional properties. One of them, named PaTu 8988s, revealed a solid growth in nude mouse xenografts with cells exhibiting only occasional polar organisation of the cytoplasm. In general, no apical or basolateral plasma membrane domains could be distinguished and the sparse organelles were randomly distributed throughout the cytoplasm. Secretory products, such as mucin, were weakly stained histochemically or were completely absent. Transglutaminase (TGase) activity used as a marker for cellular differentiation was low in these cells. The other cell line, named PaTu 8988t, grew tumors composed of tubular structures when injected subcutaneously into nude mice. Cells were polarized with distinct apical and basolateral plasma membranes and the cytoplasmatic organelles were arranged with the nucleus in the lower part of the cell, while the apical cytoplasm contained the Golgi complex and numerous secretion granules. A high content of mucin was stained histochemically and transglutaminase activity was ten times higher than in PaTu 8988s. Comparing the chromosome number per metaphase plate, both cell lines showed a major peak, with 45-55 chromosomes per metaphase plate in PaTu 8988s and about 110-120 chromosomes per metaphase plate in PaTu 8988t. When the two cell lines were injected intravenously into the tail vein of nude mice, only PaTu 8988s developed metastases localized exclusively in the lung, whereas PaTu 8988t produced no metastases in any organ. We conclude, that two cell lines exhibiting different grades of differentiation as well as a different potency to metastasize can be established from the same primary tumor, and that these cell lines represent a suitable model for further study of the cell biology of human pancreatic adenocarcinoma.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Establishment and characterisation of two cell lines with different grade of differentiation derived from one primary human pancreatic adenocarcinoma. 134 91

The Dunning tumor, originally described as a carcinoma of the rat dorsal prostate, has for long been used as an experimental model of prostatic cancer. We have recently presented a number of morphological findings that are incompatible with the prostatic origin of the H-subline of the Dunning tumor. In this paper, biochemical and immunohistochemical markers of rat prostate and mammary gland are studied in the R-3327 Dunning H tumor. Pieces of the H tumor were inoculated in male or lactating female rats. The electrophoretic protein pattern of Dunning tumor extracts was more similar to that of the mammary gland than the dorsolateral prostate. Proteins selectively appearing after metabolic labeling in Dunning tumors grown in lactating rats corresponded to labeled proteins in mammary glands from the same animals. Secretory proteins typical of the lateral prostate (SVS II) and dorsal prostate (transglutaminase) could not be detected immunohistochemically in the Dunning tumor. Western blot studies of tumor extracts and slot blot analysis of RNA preparations from the tumor confirmed the absence of SVS II and prostate specific transglutaminase from the Dunning tumor. On the other hand, the presence of mammary gland proteins such as milk fat globule membrane proteins, lactoperoxidase and lactalbumin were detected in the Dunning tumor by immunohistochemistry and Western blotting, but were absent from the dorsolateral prostate. Transferrin-mRNA, expressed in the male urogenital tract and also in the liver and other tissues, was detected in the mammary gland and Dunning tumor, but not in the dorsolateral prostate. The absence of mammary gland secretory beta-casein in the Dunning tumor was related to the elevated Ha-ras oncogene expression in the tumor, previously reported to suppress casein expression. The findings clearly demonstrate that the prostate cannot be the origin of the Dunning tumor, presently being used in prostatic cancer research. The designation prostatic adenocarcinoma for this tumor is therefore invalid. Furthermore, the data support our view that mammary gland might be the origin of the Dunning tumor, although the derivation from the bulbourethral or the parotid glands cannot strictly be excluded.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Arguments against the prostatic origin of the R-3327 Dunning H tumor. 135 78

Many Drosophila genes have now been identified with substantial sequence similarity to vertebrate protooncogenes and growth factors. Some of these have been isolated directly by cross-hybridization with vertebrate probes and some have been recognized in the sequences of genes cloned because of their intiguing mutant phenotypes. An example of a gene isolated for its interesting development functions but with homology to a vertebrate growth factor is the Drosophila decapentaplegic gene (dpp). An example of a Drosophila gene isolated by virtue of its sequence conservation is the vgr/60A gene. Both dpp and vgr/60A are members of the transforming growth factor-beta family and are most similar to the human bone morphogenetic proteins. The regulation of the dpp gene by several different groups of pattern formation genes including the dorsal/ventral group, the terminal group, the segment polarity genes, and the homeotic genes indicates that many events in embryogenesis require the cell to cell communication mediated by the secreted dpp protein. The temporal and spatial pattern of vgr/60A expression differs from that of dpp indicating that it may be regulated by different pattern information genes. The experimental advantages of the Drosophila system should permit a better understanding of the importance of growth factor homologs in specific developmental events, aid in establishing the functional interactions between these regulatory molecules, and identify new genes that are important for the biological functions of growth factors. It is likely that some of the newly identified genes will have vertebrate homologs and the analysis of these may be helpful in studies on vertebrate development and tumor biology.
Mol Reprod Dev 1992 Jun
PMID:TGF-beta family factors in Drosophila morphogenesis. 135 53

MCF-10A cells are a spontaneously immortalized untransformed human mammary epithelial cell line. We have previously shown that overexpression of a human point-mutated c-Ha-ras proto-oncogene, the rat c-neu (c-erbB-2) proto-oncogene, or the human transforming growth factor-alpha (TGF-alpha) gene in MCF-10A cells leads to in vitro transformation of such cells. To ascertain whether the introduction of two of these genes into MCF-10A human mammary epithelial cells induces a completely tumorigenic phenotype, we infected MCF-10A Ha-ras and MCF-10A TGF-alpha cells with a recombinant retroviral vector containing the human c-erbB-2 proto-oncogene and the hygromycin-resistance gene. Ten MCF-10A TGF-alpha/c-erbB-2 (MCF-10A TE) and 10 MCF-10A Ha-ras/c-erbB-2 (MCF-10A HE) hygromycin-resistant clones were randomly selected and expanded into cell lines. MCF-10A TE and MCF-10A HE clones expressed a 10-fold to 40-fold increase in p185 erbB-2 protein levels compared with parental uninfected cells. These cells exhibited a fourfold increase in their growth rate in serum-free medium and showed a strongly reduced mitogenic response to exogenous epidermal growth factor or TGF-alpha compared with MCF-10A cells. Moreover, both MCF-10A TE and MCF-10A HE clones exhibited a fivefold to 20-fold higher cloning efficiency in soft agar than MCF-10A Ha-ras, MCF-10A c-erbB-2, or MCF-10A TGF-alpha clones. However, neither MCF-10A TE nor MCF-10A HE cells were able to grow as tumors in vivo when they were injected into nude mice. These results suggest that c-Ha-ras, c-erbB-2, and TGF-alpha genes have an additive effect on the in vitro transformation of an immortalized human mammary epithelial cell line, but that additional genetic changes such as activation of other proto-oncogenes or inactivation of a tumor suppressor gene may be necessary to elicit a fully tumorigenic phenotype.
Mol Carcinog 1992
PMID:Additive effects of c-erbB-2, c-Ha-ras, and transforming growth factor-alpha genes on in vitro transformation of human mammary epithelial cells. 135 42

Structural changes in the macromolecular targets of pharmacological agents can result in alterations in the efficacy of these agents. In previous studies, we identified a variant structural form of thymidylate synthase (TS) that is associated with relative resistance to 5-fluoro-2'-deoxyuridine, in a human colonic tumor cell line. We now report on the use of DNA transfer techniques to examine directly the effects of each TS form on drug response. TS cDNA constructs, corresponding to the normal or variant TS mRNA, were expressed in Chinese hamster lung cells or in Escherichia coli, and response to 5-fluoro-2'-deoxyuridine was determined. We observed that expression of the variant TS, which differs from the normal form by a tyrosine to histidine substitution at residue 33, confers a 4-fold level of drug resistance in the mammalian cells, as well as in bacteria. The possible role of Tyr-33 in 5-fluoropyrimidine-mediated inhibition of TS is discussed.
Mol Pharmacol 1992 Aug
PMID:A naturally occurring tyrosine to histidine replacement at residue 33 of human thymidylate synthase confers resistance to 5-fluoro-2'-deoxyuridine in mammalian and bacterial cells. 135 60

Using monoclonal antibodies (MoABs) against blood group determinants and related carbohydrate sequences, it is now possible to clarify their carcinoma-associated modulation at a molecular level. In the present study a panel of MoABs against different type 1 chain derived blood group antigens, comprising A, B, H type 1, Le(a), sialyl-Le(a) (CA 19-9), sialyl type 1 structure (CA 50), and Le(b) was used to investigate their immunoreactivity in 38 medullary carcinomas of the thyroid (MTC) and in normal thyroid tissue. The antigens were not expressed in normal follicular or C-cells but were expressed to a various extent in MTC. The studies revealed some characteristic anomalies in the frequency and patterns of tumor-associated antigen expression. The MoAB C 50 stained 32 of the 38 tumors, H type 1 (Le(d)) was demonstrated in 21 and the Le(b) antigen in 27. The Le(a)- and the A antigen were detected in 10 and 12 tumors and the B antigen in one. From the results some rules about the pathways for tumor-associated re-expression of these antigens can be deduced. Le(a) antigen expression was significantly correlated with the CA 50 and Le(b) antigens. The significant relation observed between A-, H1-, and Le(b) antigen formation in MTC suggests the existence of a carcinoma-associated fucosyltransferase committing the type 1 precursor chain along the H1-antigen pathway, and by further glycosylation to an A-, B-, or a Le(b) antigen. Comparative studies of tumor-associated H type 1 and H type 2 antigen expression revealed that H type 2 antigen synthesis was significantly related to a blood type 0 in the host. On the other hand, H1 antigen reactivity was independent of the AB0 blood type of the hosts and was also detected in H type 2 antigen-negative tumors. These findings support the proposal that even in tumor tissue, H antigen expression is still determined by the interaction of at least two different genes. Despite the occurrence of the precursor substance (CA 50) and the formation of the Le(a)- and Le(b) antigens, indicating the presence of a alpha 1,4-fucosyl-transferase (Lewis-enzyme), only two tumors showed the formation of CA 19-9. In conclusion, the investigations demonstrated the dominant re-expression of three type 1 chain-derived structures in MTC, namely H type 1, Le(b), and CA 50. These findings support the general concept demonstrated in other carcinomas, that fucosyl- and sialyltransferases are preferentially activated in MTC.(ABSTRACT TRUNCATED AT 400 WORDS)
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Blood group antigen expression in medullary carcinoma of the thyroid. An immunohistochemical study on the occurrence of type 1 chain-derived antigens. 135 24

Lectin binding patterns in ten mouse malignant fibrous histiocytoma (MFH)-like sarcomas containing eosinophilic globule (EG) cells and in granular metrial gland (GMG) cells of mouse placenta were stained with nine lectins (Con A, LCA, WGA, DBA, SBA, e-PHA, PNA, RCA-I and UEA-I) by an avidin-biotin-peroxidase-complex method. EG cells stained strongly with DBA, SBA and PNA which are specific for N-acetyl-D-galactosamine and/or D-galactose. DBA and SBA bound throughout the cytoplasm including the globules; PNA reacted preferentially at the cell surface. There was no evidence that these three lectins were reactive for immature EG cells. WGA, RCA-I and e-PHA also gave a slightly to moderately positive reaction to globules of EG cells. The results indicate that the globules contain abundant O-linked sequences of sugars, but also a few N-linked residues. MFH tumor cells showed a variable degree of binding with Con A, RCA-I, and WGA, but did not react with DBA, SBA and PNA. On the other hand, GMG cells exhibited specific affinities for DBA, SBA and PNA with staining patterns similar to those of EG cells. These findings suggest that EG and GMG cells may be of the same cellular lineage.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Eosinophilic globule cells in mouse MFH-like sarcomas: lectin histochemistry. 135 25

In order to identify potential markers of malignancy in diagnostic respiratory cytopathology, c-myc and c-erbB-2 proto-oncogene expression was studied in fine needle aspirates from 14 consecutive fresh operation tissue samples (after surgical removal) representing lung tumors and a variety of other cell samples by in situ hybridization of 35S-labeled antisense and sense RNA c-myc and c-erbB-2 specific proto-oncogene probes. All 14 lung tumors showed c-myc expression and eight also showed c-erbB-2 expression. On average, the c-myc expression was about 4 times higher than that of c-erbB-2 (P less than 0.001). c-erbB-2 expression, confirmed also as a cytoplasmic membrane-bound reactivity by immunohistochemical stainings for c-erbB-2 oncoprotein, was significantly related to adenocarcinoma (P less than 0.025), whereas increasing tumor size correlated significantly with increasing c-myc expression (P less than 0.05). On average, all the tumor cell lines showed 2-fold expression of c-myc compared with the lung tumors (P less than 0.025). c-erbB-2 expression was found in six of 11 cell lines. High c-myc proto-oncogene expression was also found in broncho-epithelial cells and alveolar macrophages, and a low expression was found in lymphocytes but not in neutrophils, while none of these cells showed c-erbB-2 proto-oncogene expression. Our results demonstrate extensive c-myc proto-oncogene expression in both malignant and non-neoplastic proliferating cells, but not in terminally differentiated cells such as neutrophils. Therefore c-myc expression must also be related to general cell proliferation and not only malignancy per se. In marked contrast, c-erbB-2 proto-oncogene expression was found only in adenocarcinoma cells, and thus can be used as a marker for malignancy in diagnostic respiratory cytopathology.
Am J Respir Cell Mol Biol 1992 Sep
PMID:Evidence by in situ hybridization that c-erbB-2 proto-oncogene expression is a marker of malignancy and is expressed in lung adenocarcinomas. 135 55

A series of novel gonadotropin releasing hormone (GnRH) and Somatostatin analogs have been developed in our laboratory and were screened for antiproliferative and signal transduction inhibitory effect. Our GnRH analog Folligen, had significant antitumor activity on DMBA induced mammary carcinomas in rats without blocking ovarian functions. The direct effect of Folligen and Buserelin has been compared on the human breast cancer cell line MDA-MB-231. Folligen was found to be more effective in inhibiting cell proliferation and significant differences were found in the signal transduction pathways activated by these analogs. Our novel Somatostatin analogs were screened for tyrosine kinase inhibition and for antiproliferative effect on human colon tumor cells and for growth hormone (GH) release inhibition in vitro and in vivo. The analog TT-2-50 was significantly more active inhibiting GH release in superfused rat pituitary cells and in vivo than native Somatostatin and it strongly inhibited tyrosine kinase and proliferation while it stimulated protein kinase C activity.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Novel antitumor peptide hormones and their effect on signal transduction. 135 11


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