ABSTRACT
Bcl10, a CARD-containing protein identified from the t(1;14)(p22;q32) breakpoint in MALT lymphomas, has been shown to induce apoptosis and activate NF-kappaB in vitro. We show that one-third of bcl10-/- embryos developed exencephaly, leading to embryonic lethality. Surprisingly, bcl10-/- cells retained susceptibility to various apoptotic stimuli in vivo and in vitro. However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation. Early tyrosine phosphorylation, MAPK and AP-1 activation, and Ca2+ signaling were normal in mutant lymphocytes, but antigen receptor-induced NF-kappaB activation was absent. Thus, Bcl10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NF-kappaB activation.
Subject(s)
Adaptor Proteins, Signal Transducing , Central Nervous System/abnormalities , NF-kappa B/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Neural Tube Defects/physiopathology , Receptors, Antigen/metabolism , Animals , Anisomycin/pharmacology , Antibody Formation/immunology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis/immunology , Apoptosis/radiation effects , B-Cell CLL-Lymphoma 10 Protein , B-Lymphocytes/immunology , Cell Division/immunology , Central Nervous System/physiology , Cisplatin/pharmacology , Enzyme Inhibitors/pharmacology , Etoposide/pharmacology , Genes, Lethal/immunology , Immunity, Cellular/immunology , Lymphocyte Activation/physiology , Mice , Mice, Knockout , NF-kappa B/immunology , Neoplasm Proteins/metabolism , Neural Tube Defects/immunology , Nucleic Acid Synthesis Inhibitors/pharmacology , Protein Synthesis Inhibitors/pharmacology , Receptors, Antigen/immunology , Signal Transduction/immunology , Staurosporine/pharmacology , T-Lymphocytes/immunologyABSTRACT
BACKGROUND: Germ-line and sporadic mutations in the tumor suppressor gene PTEN (also known as MMAC or TEP1), which encodes a dual-specificity phosphatase, cause a variety of cancers such as Cowden disease, glioblastoma, endometrial carcinoma and prostatic cancer. PTEN is widely expressed, and Cowden disease consistently affects various organ systems, suggesting that the PTEN protein must have an important, although as yet poorly understood, function in cellular physiology. RESULTS: Homozygous mutant mice lacking exons 3-5 of the PTEN gene (mPTEN3-5) had severely expanded and abnormally patterned cephalic and caudal regions at day 8.5 of gestation. Embryonic death occurred by day 9.5 and was associated with defective chorio-allantoic development. Heterozygous mPTEN3-5 mice had an increased incidence of tumors, especially T-cell lymphomas; gamma-irradiation reduced the time lapse of tumor formation. DNA analysis of these tumors revealed the deletion of the mPTEN gene due to loss of heterozygosity of the wild-type allele. Tumors associated with loss of heterozygosity in mPTEN showed elevated phosphorylation of protein kinase B (PKB, also known as Akt kinase), thus providing a functional connection between mPTEN and a murine proto-oncogene (c-Akt) involved in the development of lymphomas. CONCLUSIONS: The mPTEN gene is fundamental for embryonic development in mice, as mPTEN3-5 mutant embryos died by day 9.5 of gestation, with patterning defects in cephalic and caudal regions and defective placentation. Heterozygous mice developed lymphomas associated with loss of heterozygosity of the wild-type mPTEN allele, and tumor appearance was accelerated by gamma-irradiation. These lymphomas had high levels of activated Akt/PKB, the protein product of a murine proto-oncogene with anti-apoptotic function, associated with thymic lymphomas. This suggests that tumors associated with mPTEN loss of heterozygosity may arise as a consequence of an acquired survival advantage. We provide direct evidence of the role of mPTEN as a tumor suppressor gene in mice, and establish the mPTEN mutant mouse as an experimental model for investigating the role of PTEN in cancer progression.
Subject(s)
Genes, Tumor Suppressor , Genetic Predisposition to Disease/genetics , Lymphoma, T-Cell/genetics , Neoplasms/genetics , Phosphoric Monoester Hydrolases/genetics , Proto-Oncogenes , Sequence Deletion , Tumor Suppressor Proteins , Animals , Embryonic and Fetal Development/genetics , Exons , Female , Fetal Death/genetics , Gamma Rays , Genotype , Mice , Mice, Mutant Strains , PTEN Phosphohydrolase , Phenotype , Polymerase Chain Reaction , Pregnancy , Recombination, GeneticABSTRACT
The NEUROGENINS (NGNs) are neural-specific basic helix-loop-helix (bHLH) transcription factors. Mouse embryos lacking ngn1 fail to generate the proximal subset of cranial sensory neurons. ngn1 is required for the activation of a cascade of downstream bHLH factors, including NeuroD, MATH3, and NSCL1. ngn1 is expressed by placodal ectodermal cells and acts prior to neuroblast delamination. Moreover, NGN1 positively regulates the Delta homolog DLL1 and can be negatively regulated by Notch signaling. Thus, ngn1 functions similarly to the proneural genes in Drosophila. However, the initial pattern of ngn1 expression appears to be Notch independent. Taken together with the fact that ectopic ngn1 expression can convert ectodermal cells to neurons in Xenopus (Ma et al., 1996), these data and those of Fode et al. (1998 [this issue of Neuron]) identify ngns as vertebrate neuronal determination genes, analogous to myoD and myf5 in myogenesis.
