title: NORE1A induction by membrane-bound CD40L (mCD40L) contributes to CD40L-induced cell death and G1 growth arrest in p21-mediated mechanism.
abstract: Membrane-bound CD40L (mCD40L) but not soluble CD40L (sCD40L) has been implicated in direct cell death induction and apoptosis in CD40-expressing carcinomas. In this study, we show that mCD40L but not sCD40L induces NORE1A/Rassf5 expression in an NFκB-dependant mechanism. NORE1A expression appeared to contribute to mCD40L-induced cell death and enhance cell transition from G1 to S phase of the cell cycle in a p21-dependent mechanism. The upregulation of p21 protein was attributed to NORE1A expression, since NORE1A inhibition resulted in p21 downregulation. p21 upregulation was concomitant with lower p53 expression in the cytoplasmic fraction with no detectable increase at the nuclear p53 level. Moreover, mCD40L-induced cell death mediated by NORE1A expression appeared to be independent of mCD40L-induced cell death mediated by sustained JNK activation since NORE1A inhibition did not affect JNK phosphorylation and vice versa. The presented data allow better understanding of the mechanism by which mCD40L induces cell death which could be exploited in the clinical development of CD40-targeted anti-cancer therapies.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: T
authors.initials: T
authors.lastname: Elmetwali
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: A
authors.initials: A
authors.lastname: Salman
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: D H
authors.initials: DH
authors.lastname: Palmer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D020935:MAP Kinase Signaling System; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C454042:RASSF5 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D023201:CD40 Ligand; D020559:Monomeric GTP-Binding Proteins