UMLS:C0007097 - FACTA Search

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Query: UMLS:C0007097 (carcinoma)
152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tyrosine kinase substrate p120cas (CAS), which is structurally similar to the cell adhesion proteins beta-catenin and plakoglobin, was recently shown to associate with the E-cadherin-catenin cell adhesion complex. beta-catenin, plakoglobin, and CAS all have an Arm domain that consists of 10 to 13 repeats of a 42-amino-acid motif originally described in the Drosophila Armadillo protein. To determine if the association of CAS with the cadherin cell adhesion machinery is similar to that of beta-catenin and plakoglobin, we examined the CAS-cadherin-catenin interactions in a number of cell lines and in the yeast two-hybrid system. In the prostate carcinoma cell line PC3, CAS associated normally with cadherin complexes despite the specific absence of alpha-catenin in these cells. However, in the colon carcinoma cell line SW480, which has negligible E-cadherin expression, CAS did not associate with beta-catenin, plakoglobin, or alpha-catenin, suggesting that E-cadherin is the protein which bridges CAS to the rest of the complex. In addition, CAS did not associate with the adenomatous polyposis coli (APC) tumor suppressor protein in any of the cell lines analyzed. Interestingly, expression of the various CAS isoforms was quite heterogeneous in these tumor cell lines, and in the colon carcinoma cell line HCT116, which expresses normal levels of E-cadherin and the catenins, the CAS1 isoforms were completely absent. By using the yeast two-hybrid system, we confirmed the direct interaction between CAS and E-cadherin and determined that CAS Arm repeats 1 to 10 are necessary and sufficient for this interaction. Hence, like beta-catenin and plakoglobin, CAS interacts directly with E-cadherin in vivo; however, unlike beta-catenin and plakoglobin, CAS does not interact with APC or alpha-catenin.
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PMID:The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin. 765 99

Activation of the tyrosine kinase of the c-src gene product, pp60c-src, has been shown to occur in nearly every primary colorectal carcinoma, and is found as early as in polyps of high malignant potential. However, no studies have addressed potential pp60c-src changes which occur during progression. To examine this question, we have studied kinase activity and protein levels in 7 colonic polyps, 19 primary lesions, and 19 liver metastases relative to normal colonic mucosa. Significant increases in tyrosine kinase activity were seen as early as in colonic polyps of high malignant potential. Further increases were observed in activity and level in primary tumors. However, the greatest increases in activity and protein levels were observed in liver metastases. Additionally, six metastatic lesions were obtained in which synchronous primary tumor was resected. In each of these liver metastases, pp60c-src activity and level were significantly increased relative to the corresponding primary tumor, as well as to normal colonic mucosa. Our results demonstrate that progression of colon primary tumors to liver metastases correlates with increased pp60c-src kinase activity and protein level.
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PMID:Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. 767 9

Vitamin A or retinol is an important agent in the normal differentiation and growth of cells. Retinol is an effective inhibitor of the growth of many transformed cells in vitro and in vivo but its mechanism of action is unclear. Transforming growth factor alpha (TGF alpha) is a known mitogen. We examined the effect of retinol treatment on TGF alpha stimulation of two human mammary carcinoma cell lines, one which is growth inhibited by retinol and one which is not. Pretreatment of both cell lines for 48 hours with retinol resulted in inhibition of TGF alpha stimulation of growth. In the T47D cell line the mechanism was not related to an effect on the cellular content of TGF alpha, epidermal growth factor (EGF) receptor protein, EGF receptor mRNA, or on the binding of TGF alpha to the EGF receptor. However, TGF alpha-induced stimulation of the EGF receptor substrate, phospholipase C-gamma 1, was abrogated in the T47D cell line with retinol pretreatment. In the MDA-MB-468 cell line, pretreatment with retinol resulted in a decrease in tyrosine phosphorylation of the EGF receptor. These results suggest that pretreatment with retinol decreases cellular proliferation seen with TGF alpha treatment by altering phospholipase C-gamma 1 response and/or EGF receptor tyrosine kinase activity. Alteration of phospholipase C-gamma 1 activity does not appear to be responsible for the inhibition of cell growth seen in the absence of TGF alpha stimulation.
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PMID:Pretreatment with vitamin A inhibits transforming growth factor alpha stimulation of human mammary carcinoma cells. 768 67

The c-src proto-oncogene has been implicated in the progression of primary human colorectal carcinoma to hepatic metastasis. To determine if increased pp60c-src tyrosine kinase activity is a colon-specific phenomenon present in colorectal metastases to all sites, the pp60c-src-specific kinase activity of noncolon tumor metastases to the liver was compared to that of colorectal liver metastases. Activity of extrahepatic colon carcinoma metastases was compared to that of colorectal liver metastases as well as that of normal colonic mucosa. The specific activity of pp60c-src in multiple synchronous metastases from colon carcinoma was also examined. Tyrosine kinase activity was determined by immune complex kinase assay; protein levels were determined by immunoblotting. Specific activity was calculated for each group by dividing the total activity by protein level. Colon carcinoma metastases to the liver had significantly (P < 0.04) increased pp60c-src activity with an average 2.2-fold increase over normal mucosa. In contrast, noncolon tumor metastases to the liver showed minimal pp60c-src kinase activity. Extrahepatic colorectal metastases demonstrated significantly increased (P < 0.005) pp60c-src activity with an average 12.7-fold increase over normal mucosa. When compared to colon liver metastases, extrahepatic colorectal tumor metastases show a significant difference in activity (P < 0.05) with an average 5.7-fold increase. Examination of multiple synchronous colon carcinoma metastases confirmed these results. In summary, we conclude that (1) the activation of pp60c-src between primary tumors and metastases is specific to colon metastases, and (2) although pp60c-src activity is significantly increased in colorectal metastases, site-specific differences in the magnitude of activity are evident.
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PMID:Site-specific differences in pp60c-src activity in human colorectal metastases. 768 14

Interleukin-1 (IL-1) induces programmed growth arrest in human melanoma cells, A375-C6. IL-1 action in these cells is associated with induction of a cell type-specific immediate-early (IE) gene expression program characterized by strong, rapid, and sustained induction of gro-alpha and gro-beta, but transient induction of c-jun, IRG-9, and NAK-1, and lack of induction of c-myc. With the exception of gro-alpha and gro-beta, these IE genes are also associated with growth-stimulatory responses in the melanoma cells, suggesting that the gro-genes may play key roles in the growth arrest action of the cytokine. To elucidate the early intracellular signals associated with IL-1 action, we are studying the second messenger signals and transcription factors required for induction of gro-genes. Here, we present evidence that IL-1-inducible gro-gene expression is dependent on tyrosine kinase signaling. Using gel retardation and transient expression assays, we show that IL-1 causes protein tyrosine phosphorylation-dependent activation of NF-kappa B enhancer binding protein, which then induces transcription of the gro-genes via an NF-kappa B site located 76 base pairs upstream from the cap site. IL-1-activated protein tyrosine phosphorylation is also required for gro-gene induction in human cervical carcinoma cells, HeLa; human fibroblast cells, WI-38; and mouse fibroblast cells, L929. Thus, in diverse cell types, IL-1 induces gro-genes via tyrosine kinase-dependent signals.
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PMID:Interleukin-1-inducible expression of gro-beta via NF-kappa B activation is dependent upon tyrosine kinase signaling. 768 36

To examine the role of Src-related proteins in human colon carcinoma we measured the tyrosine kinase activity of pp60c-src (Src), p62c-yes (Yes), p56lck (Lck), p59fyn (Fyn), p59hck (Hck), p56lyn (Lyn) and p55c-fgr (Fgr) from colonic cells. Yes activity, similar to that of Src, was 10-20 fold higher in three of five colon carcinoma cell lines and fivefold higher in 10 of 21 primary colon cancers than that in normal colonic cells. Lck activity was present in COLO 205 cells, otherwise Lck, Fyn, Hck, Lyn and Fgr activities were not detected in any of the carcinoma cell lines or cancers tested. Increased Yes activity, like that of Src, was due mostly to increased protein levels and not to an apparent decrease in phosphorylation of Tyr 537, the major mechanisms known to deregulate enzymatic activity. Only those colon carcinoma cell lines with elevated Src and/or Yes tyrosine kinase activity as measured in vitro had elevated levels of three tyrosine-phosphorylated proteins as measured in vivo. Thus, colon carcinoma cells contain active tyrosine kinases and/or inactive tyrosine phosphatases not present in normal colonic cells, and Src and Yes appear to be active kinases in the carcinoma cells. These data, together with those demonstrating decreased Src activity in fully differentiated enterocytes, suggest that down regulation of Src-related tyrosine kinases is important for differentiation, and/or deregulation of the kinases is important for growth and transformation of intestinal epithelial cells.
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PMID:c-Yes tyrosine kinase activity in human colon carcinoma. 769 Sep 25

Both EGF and insulin, or IGF, stimulate the growth of many cell types by activating receptors that contain tyrosine kinase activities. A monoclonal antibody (mAb 225) against the EGF receptor produced in this laboratory has been shown to competitively inhibit EGF binding and block activation of receptor tyrosine kinase. Here we report that a human colorectal carcinoma cell line, DiFi, which expresses high levels of EGF receptors on plasma membranes, can be induced to undergo G1 cell cycle arrest and programmed cell death (apoptosis) when cultured with mAb 225 at concentrations that saturate EGF receptors. Addition of IGF-1 or high concentrations of insulin can delay apoptosis induced by mAb 225, while the G1 arrest cannot be reversed by either IGF-1 or insulin. Insulin/IGF-1 cannot activate EGF receptor tyrosine kinase that has been inhibited by mAb 225. Moreover, an mAb against the IGF-1 receptor, which has little direct effect on DiFi cell growth, can block the capacity of insulin/IGF-1 to delay apoptosis induced by mAb 225, suggesting that the insulin/IGF-1-mediated delay of apoptosis is acting through the IGF-1 receptor. In contrast, insulin/IGF-1 cannot delay the apoptosis caused by the DNA damaging agent, cisplatin. The results indicate that EGF receptor activation is required both for cell cycle progression and for prevention of apoptosis in DiFi cells, and that a signal transduction pathway shared by receptors for insulin/IGF-1 and EGF may be involved in regulating apoptosis triggered by blockade of the EGF receptor.
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PMID:Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. 770 97

PTC-1, the predominant form of PTC oncogene in human papillary thyroid carcinoma, encodes a fusion protein containing the N-terminus of H4 (D10S170) fused 5' to the ret tyrosine kinase domain. Accordingly, the PTC-1 expression is driven by the H4 gene promoter. Our study showed that H4 is expressed in various human tissues, including thyroid. Furthermore, we have localized the transcriptional start sites of H4 to a region 100 to 190 bp upstream of the translation initiation site (ATG) by primer extension assay, and the H4 promoter to a region within 259 bp upstream of the ATG site by luciferase assay. Interestingly, protein sequence analysis indicated a potential coiled-coil domain in the N-terminal region of H4. Indeed, oligomerization was demonstrated by an in vitro assay with recombinant proteins containing this region. As dimerization is considered to be a crucial step for receptor tyrosine kinase activation, we hypothesize that both unscheduled expression of ret tyrosine kinase and constitutive oligomerization of PTC-1 proteins are responsible for PTC-1 transforming activity in thyroid.
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PMID:Characterization of the promoter region and oligomerization domain of H4 (D10S170), a gene frequently rearranged with the ret proto-oncogene. 775 54

The Epstein-Barr virus (EBV)-encoded LMP1 protein is an important component of the process of transformation by EBV. LMP1 is essential for transformation of B lymphocytes, most likely because of its profound effects on cellular gene expression. Although LMP1 is expressed in the majority of nasopharyngeal carcinoma (NPC) tumors, the effect of LMP1 on cellular gene expression and its contribution to the development of malignancy in epithelial cells is largely unknown. In this study the effects of LMP1 on the expression and tyrosine kinase activity of the epidermal growth factor receptor (EGFR) were investigated in C33A human epithelial cells. Stable or transient expression of LMP1 in C33A cells increased expression of the EGFR at both the protein and mRNA levels. In contrast, expression of the EGFR was not induced by LMP1 in EBV-infected B lymphocytes. Stimulation of LMP1-expressing C33A cells with epidermal growth factor (EGF) caused rapid tyrosine phosphorylation of the EGFR (pp170) as well as several other proteins, including pp120, pp85, pp75, and pp55, indicating that the EGFR induced by LMP1 is functional. LMP1 also induced expression of the A20 gene in C33A epithelial cells. In C33A cells, LMP1 expression increased the proliferative response to EGF, as LMP1-expressing C33A cells continued to increase in number when plated in serum-free media supplemented with EGF, while the neo control cells exhibited very low levels of viability and did not proliferate. Immunoblot analysis of protein extracts from nude mouse-passaged NPC tumors also demonstrated that the EGFR is overexpressed in primary NPC tumors as well as those passaged in nude mice. This study suggests that the alteration in the growth patterns of C33A cells expressing LMP1 is a result of increased proliferative signals due to enhanced EGFR expression, as well as protection from cell death due to LMP1-induced A20 expression. The induction of EGFR and A20 by LMP1 may be an important component of EBV infection in epithelial cells and could contribute to the development of epithelial malignancies such as NPC.
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PMID:The Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor. 776 1

To study the growth control of human thyroid cells in different stages of differentiation, we established two human thyroid cell lines of adenomatous goiter and papillary carcinoma. A 59-year-old female patient with adenomatous goiter was operated in September 1991, and a 27-year-old female patient with papillary carcinoma in May 1990. The thyroid cell lines were established by successive passage without cellular or genetic manipulations such as fusing other cell lines or oncogenic viral infection. These cell lines, human adenomatous goiter cells (hAG) and human papillary thyroid carcinoma cells (hPTC), exhibited a flattened polygonal shape and proliferated as a monolayer in cell culture. The doubling time of the hAG cells was 60 h in Ham's F12 medium supplemented with 10% fetal bovine serum, and that of the hPTC cells, 18 h in the same medium. Both cell lines expressed mRNA for TSH receptor and secreted cAMP into the medium during incubation with thyrotropin (TSH) at concentrations as low as 0.01 mU/mL. The effects of activators of protein kinase A (PKA), protein kinase C (PKC), tyrosine kinase (TK), and estradiol (E2) on proliferation of the hAG cells and the hPTC cells were assessed by measuring cellular DNA content in 24-well plates with diaminobenzoic acid. TSH stimulated proliferation of the hAG cells, but it inhibited proliferation of the hPTC cells. Since TSH activates two signaling pathways, the adenyl cyclase-PKA system and phospholipase C-PKC system, we tested effects of dibutylyl cAMP (dBC) and phorbol myristate 13-acetate (PMA), separately. dBC stimulated proliferation of the hAG cells, but it inhibited that of the hPTC cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Different growth control of the two human thyroid cell lines of adenomatous goiter and papillary carcinoma. 778 32

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