title: The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells.
abstract: Mast cells play critical roles in the regulation of inflammation. One characteristic feature of mast cells is their relatively long lifespan in vivo. Members of the Bcl-2 protein family are regulators of cell survival and apoptosis, where the BH3-only proteins are critical proapoptotic proteins. In this study we investigated the role of the BH3-only proteins Noxa, Bad, Bim, Bmf, Bid, and Puma in apoptosis of mucosal-like mast cells (MLMCs) and connective tissue-like mast cells (CTLMCs). We demonstrate that Puma is critical for the induction of mast-cell death following cytokine deprivation and treatment with the DNA-damaging agent etoposide in MLMCs and CTLMCs. Using p53-/- mast cells, we found that cytokine deprivation-induced apoptosis, in contrast to that elicited by etoposide, is p53-independent. Interestingly, mast cells deficient in FOXO3a, previously proposed as a transcription factor for Puma induction in response to growth factor deprivation, were markedly resistant to cytokine withdrawal compared with wild-type cells. Moreover, overexpression of phosphorylation-deficient, constitutively active FOXO3a caused an up-regulation of Puma. In conclusion, our data demonstrate a pivotal role for Puma in the regulation of cytokine deprivation-induced mast-cell apoptosis and suggest a plausible role for Puma in the regulation of mast cell numbers in vivo.
authors.affiliation: Department of Medicine, Clinical Immunology and Allergy Unit, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Ekoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
authors.forename: Maria
authors.initials: M
authors.lastname: Engström
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D016207:Cytokines / Q000172:deficiency*; D005047:Etoposide / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology; D005786:Gene Expression Regulation; D016158:Genes, p53 / Q000502:physiology; D008407:Mast Cells / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D005047:Etoposide