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Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice.

ABSTRACT: Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated "mature phenotype" lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver of lymphomagenesis within the thymus characterized by overexpression of the c-myc oncogene. In an otherwise normal thymic environment, PTEN-deficient T cell lymphomas invariably harbored RAG-dependent reciprocal t(14:15) chromosomal translocations involving the T cell receptor alpha/delta locus and c-myc, and their survival and growth was TCR dependent, but Notch independent. However, lymphomas occurred even if TCR recombination was prevented, although these lymphomas were less mature, arose later in life, and, importantly, were dependent upon Notch pathways to upregulate c-myc expression. In contrast, using the complementary methods of early thymectomy and adoptive transfers, we found that PTEN-deficient mature T cells were unable to undergo malignant transformation but were sufficient for the development of autoimmunity. These data suggest multiple and distinct regulatory roles for PTEN in the molecular pathogenesis of lymphoma and autoimmunity.

SUBMITTER: Liu X

PROVIDER: S-EPMC2898609 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice.

Liu Xiaohe X Karnell Jodi L JL Yin Bu B Zhang Ruan R Zhang Jidong J Li Peiying P Choi Yongwon Y Maltzman Jonathan S JS Pear Warren S WS Bassing Craig H CH Turka Laurence A LA

The Journal of clinical investigation 20100701 7

Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated "mature phenotype" lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver ...[more]

PMID: 20516645

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Project description:Phosphatase and tensin homolog deleted on chromosome ten (PTEN) has been found to regulate longevity through the PI3K/Akt/FoxO pathway and maintenance of genome integrity in worms, flies, and mammals. However, limited information is available on the roles of PTEN in longevity of aquatic animals. Here we extended this paradigm using two closely related Argopecten scallops, Argopecten purpuratus, and Argopecten irradians, with significantly distinct life spans, which are commercially important bivalve species for fishery and aquaculture in China, United States, Peru, and Chile. The ORFs of the ApPTEN and AiPTEN were 1,476 and 1,473 bp, which encoded 491 and 490 amino acids, respectively. There were 48 synonymous and 16 non-synonymous SNPs and one InDel of three nucleotides between ApPTEN and AiPTEN, resulting in variations in 15 amino acids and lack of S453 in AiPTEN. Differences in conformation and posttranslational modification were predicted between ApPTEN and AiPTEN, which may indicate different activities of ApPTEN and AiPTEN. When the animals were subjected to nutrition restriction, the expression of both ApPTEN and AiPTEN was upregulated, with AiPTEN responded faster and more robust than ApPTEN. Ionizing radiation induced significantly elevated expression of ApPTNE but not AiPTEN in the adductor muscle, and the mortality rate of A. purpuratus was significantly lower than that of A. irradians, indicating that ApPTNE may play a protective role by maintaining the genome integrity. RNAi of ApPTNE significantly downregulated the expression of its downstream regulated genes known to favor longevity, such as FoxO, Mn-SOD, and CAT. These results indicated that PTEN may contribute to the longevity of A. purpuratus through regulation of nutrient availability and genomic stability, probably via PI3K/Akt/FoxO pathway. Our study may provide new evidence for understanding of the conservative functions of PTEN in regulation of lifespan in animals and human, and it may also benefit the selection of scallops strains with long lifespan and thus larger size.

Dataset Information

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice.

Publications

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice.

Similar Datasets

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