title: cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response.
abstract: Activation and proliferation of T cells are tightly regulated during the immune response. We show here that kinetics of proliferation of PHA activated T cells follows the expression of cMyc. Expression of p53 is also elevated and remains high several days after activation. To investigate the role of p53 in activated T cells, its expression was further elevated with nultin-3 treatment, a small molecule that dissociates the E3 ubiquitin protein ligase MDM2 from p53. Concomitantly, cMyc expression and proliferation decreased. At the other end of the cMyc-p53 axis, inhibition of cMyc with 10058-F4 led to down regulation of p53, likely through the lower level of cMyc induced p14ARF, which is also known to dissociate the p53-MDM2 complex. Both compounds induced cell cycle arrest and apoptosis. We conclude that the feedback regulation between cMyc and p53 is important for the T cell homeostasis. We also show that the two compounds modulating p53 and cMyc levels inhibited proliferation without abolishing the cytotoxic function, thus demonstrating the dichotomy between proliferation and cytotoxicity in activated T cells.
authors.affiliation: a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.|b Department of Oncology-Pathology , Cancer Center Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden.
authors.forename: Harsha S
authors.initials: HS
authors.lastname: Madapura
authors.affiliation: a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Salamon
authors.affiliation: b Department of Oncology-Pathology , Cancer Center Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden.
authors.forename: Klas G
authors.initials: KG
authors.lastname: Wiman
authors.affiliation: a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lain
authors.affiliation: a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Klein
authors.affiliation: a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Noémi
authors.initials: N
authors.lastname: Nagy
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007109:Immunity / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008954:Models, Biological; D010879:Piperazines / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch; D013844:Thiazoles; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D013755:Tetradecanoylphorbol Acetate
keywords: 10058-F4; T cells; apoptosis; cMyc; nutlin-3; p53