title: SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells.
abstract: We have previously deleted both endogenous copies of the clathrin heavy-chain gene in the chicken pre B-cell-line DT40 and replaced them with clathrin under the control of a tetracycline-regulatable promoter (Tet-Off). The originally derived cell-line DKO-S underwent apoptosis when clathrin expression was repressed. We have also described a cell-line DKO-R derived from DKO-S cells that was less sensitive to clathrin-depletion. Here we show that the restriction of transferrin uptake, resulting in iron deprivation, is responsible for the lethal consequence of clathrin-depletion. We further show that the DKO-R cells have up-regulated an anti-apoptotic survival pathway based on the chemokine SDF-1 and its receptor CXCR4. Our work clarifies several puzzling features of clathrin-depleted DT40 cells and reveals an example of how SDF-1/CXCR4 signalling can abrogate pro-apoptotic pathways and increase cell survival. We propose that the phenomenon described here has implications for the therapeutic approach to a variety of cancers.
authors.affiliation: The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Alena
authors.initials: A
authors.lastname: Pance
authors.affiliation: Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Morrissey-Wettey
authors.affiliation: Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Craig
authors.affiliation: Roslin Institute, Roslin, Midlothian, Scotland, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Downing
authors.affiliation: Roslin Institute, Roslin, Midlothian, Scotland, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Talbot
authors.affiliation: Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Antony P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D002645:Chickens; D033922:Clathrin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D000090463:Iron Deficiencies; D020411:Oligonucleotide Array Sequence Analysis; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013752:Tetracycline / Q000494:pharmacology; D014168:Transferrin / Q000235:genetics / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; D003470:Culture Media; D019718:Receptors, CXCR4; D014168:Transferrin; D033922:Clathrin Heavy Chains; D013752:Tetracycline