title: Regulation of mature T lymphocyte proliferation and differentiation by Par-4.
abstract: The genetic inactivation of the atypical protein kinase C (aPKC) inhibitor, Par-4, gives rise to increased NF-kappaB activation and decreased stimulation of JNK in embryo fibroblasts. Here we have characterized the immunological phenotype of the Par-4(-/-) mice and found that the loss of this gene leads to an increased proliferative response of peripheral T cells when challenged through the TCR. This is accompanied by a higher increase in cell cycle entry and inhibition of apoptosis, with enhanced IL-2 secretion but normal CD25 synthesis. Interestingly, the TCR-triggered activation of NF-kappaB was augmented and that of JNK was severely abrogated. Consistent with previous data from knock outs of different JNKs, NFATc1 activation and IL-4 secretion were augmented in the Par-4-deficient CD4+ T cells, suggesting that the loss of Par-4 drives T-cell differentiation towards a Th2 response. This is compelling evidence that Par-4 is a novel modulator of the immune response through its ability to impact aPKC activity, which translates into lower JNK signaling.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Canto Blanco, 28049 Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Lafuente
authors.forename: Pilar
authors.initials: P
authors.lastname: Martin
authors.forename: Isabel
authors.initials: I
authors.lastname: Garcia-Cao
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division / Q000235:genetics; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D011948:Receptors, Antigen, T-Cell; C101296:prostate apoptosis response-4 protein; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases