{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["102(4)"],"submitter":["Mahalingam D"],"pubmed_abstract":["<h4>Background</h4>Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour cell apoptosis by binding to death receptor 4 (DR4) and DR5. DR4 and DR5 activation however can also induce inflammatory and pro-survival signalling. It is not known how these different cellular responses are regulated and what the individual role of DR4 vs DR5 is in these processes.<h4>Methods</h4>DNA microarray study was carried out to identify genes differentially expressed after DR4 and DR5 activation. RT-PCR and western blotting was used to examine the expression of early growth response gene-1 (Egr-1) and the proteins of the TRAIL signalling pathway. The function of Egr-1 was studied by siRNA-mediated knockdown and overexpression of a dominant-negative version of Egr-1.<h4>Results</h4>We show that the immediate early gene, Egr-1, regulates TRAIL sensitivity. Egr-1 is constitutively expressed in colon cancer cells and further induced upon activation of DR4 or DR5. Our results also show that DR4 mediates a type II, mitochondrion-dependent apoptotic pathway, whereas DR5 induces a mitochondrion-independent, type I apoptosis in HCT15 colon carcinoma cells. Egr-1 drives c-FLIP expression and the short splice variant of c-FLIP (c-FLIP(S)) specifically inhibits DR5 activation.<h4>Conclusion</h4>Selective knockdown of c-FLIP(S) sensitises cells to DR5-induced but not DR4-induced apoptosis and Egr-1 exerts an effect as an inhibitor of the DR5-induced apoptotic pathway, possibly by regulating the expression of c-FLIP(S)."],"journal":["British journal of cancer"],"pagination":["754-64"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC2837577"],"repository":["biostudies-literature"],"pubmed_title":["Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells."],"pmcid":["PMC2837577"],"pubmed_authors":["Natoni A","Mahalingam D","Samali A","Keane M","Szegezdi E"],"additional_accession":[]},"is_claimable":false,"name":"Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells.","description":"<h4>Background</h4>Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour cell apoptosis by binding to death receptor 4 (DR4) and DR5. DR4 and DR5 activation however can also induce inflammatory and pro-survival signalling. It is not known how these different cellular responses are regulated and what the individual role of DR4 vs DR5 is in these processes.<h4>Methods</h4>DNA microarray study was carried out to identify genes differentially expressed after DR4 and DR5 activation. RT-PCR and western blotting was used to examine the expression of early growth response gene-1 (Egr-1) and the proteins of the TRAIL signalling pathway. The function of Egr-1 was studied by siRNA-mediated knockdown and overexpression of a dominant-negative version of Egr-1.<h4>Results</h4>We show that the immediate early gene, Egr-1, regulates TRAIL sensitivity. Egr-1 is constitutively expressed in colon cancer cells and further induced upon activation of DR4 or DR5. Our results also show that DR4 mediates a type II, mitochondrion-dependent apoptotic pathway, whereas DR5 induces a mitochondrion-independent, type I apoptosis in HCT15 colon carcinoma cells. Egr-1 drives c-FLIP expression and the short splice variant of c-FLIP (c-FLIP(S)) specifically inhibits DR5 activation.<h4>Conclusion</h4>Selective knockdown of c-FLIP(S) sensitises cells to DR5-induced but not DR4-induced apoptosis and Egr-1 exerts an effect as an inhibitor of the DR5-induced apoptotic pathway, possibly by regulating the expression of c-FLIP(S).","dates":{"release":"2010-01-01T00:00:00Z","publication":"2010 Feb","modification":"2025-04-29T10:30:12.233Z","creation":"2019-03-27T00:29:19Z"},"accession":"S-EPMC2837577","cross_references":{"pubmed":["20087343"],"doi":["10.1038/sj.bjc.6605545"]}}