title: p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP.
abstract: Lack of functional SAP protein, due to gene deletion or mutation, is the cause of X-linked lymphoproliferative disease (XLP), characterized by functionally impaired T and NK cells and a high risk of lymphoma development. We have demonstrated earlier that SAP has a pro-apoptotic function in T and B cells. Deficiency of this function might contribute to the pathogenesis of XLP. We have also shown that SAP is a target of p53 in B cell lines. In the present study, we show that activated primary T cells express p53, which induces SAP expression. p53 is functional as a transcription factor in activated T cells and induces the expression of p21, PUMA and MDM2. PARP cleavage in the late phase of activation indicates that T cells expressing high levels of SAP undergo apoptosis. Modifying p53 levels using Nutlin-3, which specifically dissociates the MDM2-p53 interaction, was sufficient to upregulate SAP expression, indicating that SAP is a target of p53 in T cells. We also demonstrated p53's role as a transcription factor for SAP in activated T cells by ChIP assays. Our result suggests that p53 contributes to T cell homeostasis through the induction of the pro-apoptotic SAP. A high level of SAP is necessary for the activation-induced cell death that is pivotal in termination of the T cell response.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Harsha S
authors.initials: HS
authors.lastname: Madapura
authors.forename: Daniel
authors.initials: D
authors.lastname: Salamon
authors.forename: Klas G
authors.initials: KG
authors.lastname: Wiman
authors.forename: Sonia
authors.initials: S
authors.lastname: Lain
authors.forename: George
authors.initials: G
authors.lastname: Klein
authors.forename: Eva
authors.initials: E
authors.lastname: Klein
authors.forename: Noémi
authors.initials: N
authors.lastname: Nagy
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2