Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several components of the eukaryotic protein synthesis apparatus have been associated with oncogenic transformation of cells. Overexpression of the initiation factor eIF4E occurs in a variety of human tumours. The aim of this study was to determine the level of expression and the phosphorylation state of eIF4E and 4E-binding protein 1 (4E-BP1) in gastrointestinal cancer, and to ascertain whether or not these factors can be used as diagnostic or prognostic markers within this type of cancer. The eIF4E levels were significantly higher in tumours compared with normal tissue (51. 5+/-4.4 vs 30.9+/-2.5 arbitrary units (A.U.)/mg of protein, p<0.001). However, phosphorylated eIF4E did not change in stomach cancers and decreased in colorectal cancers (67.1+/-1.2 vs 60.8+/-2.8%, p<0.05). 4E-BP1 expression increased in most of the gastrointestinal cancers studied. In addition, an inverse correlation between 4E-BP1 elevation and N and M stages was found, showing significant higher elevation of 4E-BP1 in Node-negative patients (11.21+/-5.74 vs 4. 03+/-2.36 n-fold, p<0.05) as well as in patients without distant metastasis (8.41+/-3.29 vs 0.97+/-0.35 n-fold, p<0.05). These results suggest that 4E-BP1 could function as a tumour suppressor. Moreover, the data show a significant dephosphorylation of 4E-BP1 in gastrointestinal tumours that correlated with an increase in the association of 4E-BP1 and eIF4E indicating a lower availability to eIF4E to recruit to the ribosomes. Our results support a possible role of 4E-BP1 as a prognostic factor in gastrointestinal carcinoma.
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PMID:4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. 1078 60

The development of gastrointestinal cancer in humans and animals occurs through a consecutive series of stages termed initiation, promotion and progression. The characterization of each of these stages has been elucidated in several model systems as well as in human neoplasms. Both single, putatively initiated cells and preneoplastic foci have been identified by marker protein differences as well as by mutational changes. The promotion stage involves the clonal expansion of single initiated cells. Such expansion can be rapidly reversed by a variety of means, of which acute fasting (as exemplified in rat hepatocarcinogenesis) is among the most rapid and efficient. This reversal involves a selective apoptosis of preneoplastic cells and preneoplastic lesions, associated with a marked increase in expression of the proto-oncogene c-myc. Transition of cells from the stage of promotion to that of progression initially involves specific karyotypic alterations, as noted in both the rat liver model and human colon carcinogenesis. In the former, the transition appears to be associated with enhanced expression of the H119 imprinted putative tumour suppressor gene. Thus, the use of model systems may be applied directly to the human circumstance, increasing the potential both for rational prevention of gastrointestinal neoplasia and for new approaches to the therapy of neoplastic disease in the progression stage.
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PMID:Review article: the stages of gastrointestinal carcinogenesis--application of rodent models to human disease. 1080 17

SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.
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PMID:Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. 1679 Dec 1