Nfatc2 and Tob1 Have Non-Overlapping Function in T Cell Negative Regulation and Tumorigenesis

May, Sarah L.; Zhou, Qing; Lewellen, Mitzi; Carter, Cristan M.; Coffey, David G.; Highfill, Steven L.; Bucher, Christoph; Matise, Ilze; Morse, Herbert C.; O’Sullivan, M. Gerard; Schutten, Melissa M.; Johnson, Carey K.; Bellgrau, Donald; Blazar, Bruce R.; Modiano, Jaime F.

doi:10.1371/journal.pone.0100629

Cited by 14 publications

(15 citation statements)

References 44 publications

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“… 4 Recently, it was shown that NFAT1 −/− mice also develop spontaneous B-cell lymphomas. 123 Taken together, these results support an opposite role for NFAT1 and NFAT2 in the regulation of tumorigenesis.…”

Section: Nfat and Tumorigenesismentioning

confidence: 68%

Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player

et al. 2016

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The NFAT (nuclear factor of activated T cells) family of transcription factors consists of four Ca2+-regulated members (NFAT1–NFAT4), which were first described in T lymphocytes. In addition to their well-documented role in T lymphocytes, where they control gene expression during cell activation and differentiation, NFAT proteins are also expressed in a wide range of cells and tissue types and regulate genes involved in cell cycle, apoptosis, angiogenesis and metastasis. The NFAT proteins share a highly conserved DNA-binding domain (DBD), which allows all NFAT members to bind to the same DNA sequence in enhancers or promoter regions. The same DNA-binding specificity suggests redundant roles for the NFAT proteins, which is true during the regulation of some genes such as IL-2 and p21. However, it has become increasingly clear that different NFAT proteins and even isoforms can have unique functions. In this review, we address the possible reasons for these distinct roles, particularly regarding N- and C-terminal transactivation regions (TADs) and the partner proteins that interact with these TADs. We also discuss the genes regulated by NFAT during cell cycle regulation and apoptosis and the role of NFAT during tumorigenesis.

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Section: Nfat and Tumorigenesismentioning

confidence: 68%

Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player

et al. 2016

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“…Sikander et al [51] demonstrated that there may be a potential association between polymorphisms in the (SERT) gene promoter and UC, thus STX3 seems to be important for UC pathogenesis. Considering NFATC2, we know that it is a transcription factor with pleotropic roles [52]. Remarkably, the existing data suggest an important cell-intrinsic role for NFAT family transcription factors in intrinsic negative T cell regulation and Weigmann et al [53] supported that oxazolone-induced ulcerative colitis and progression to colon cancer are attenuated in NFATC2 KO mice due to ineffective production of IL-6.…”

Section: Discussionmentioning

confidence: 99%

Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: a systems bioinformatics approach

et al. 2019

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Background: Crohn's disease (CD) and Ulcerative colitis (UC) are the two main entities of inflammatory bowel disease (IBD). Previous works have identified more than 200 risk factors (including loci and signaling pathways) in populations of predominantly European ancestry. Our study was conducted on an extended population-specific cohort of 573 Greek IBD patients (364 CD and 209 UC) and 445 controls. Aims: To highlight the different genetic and functional background of IBD and its phenotypes, utilizing contemporary systems bioinformatics methodologies. Methods: Disease-associated SNPs, obtained via our own 89 loci IBD risk GWAS panel, were detected with the whole genome association analysis toolset PLINK. These SNPs were used as input for 2 novel and different pathway analysis methods to detect functional interactions. Specifically, PathwayConnector was used to create complementary networks of interacting pathways whereas; the online database of protein interactions STRING provided protein-protein association networks and their derived pathways. Network analyses metrics were employed to identify proteins with high significance and subsequently to rank the signaling pathways those participate in. Results: The reported complementary pathway and enriched protein-protein association networks reveal several novel and well-known key players, in the functional background of IBD like Toll-like receptor, TNF, Jak-STAT, PI3K-Akt, T cell receptor, Apoptosis, MAPK and B cell receptor signaling pathways. IBD subphenotypes are found to have distinct genetic and functional profiles which can contribute to their accurate identification and classification. As a secondary result we identify an extended network of diseases with common molecular background to IBD. Conclusions: IBD's burden on the quality of life of patients and intricate functional background presents us constantly with new challenges. Our data and methodology provide researchers with new insights to a specific population, but also, to possible differentiation markers of disease classification and progression. This work, not only provides new insights into the interplay among IBD risk variants and their related signaling pathways, elucidates the mechanisms underlying IBD and its clinical sequelae, but also, introduces a generalized bioinformatics-based methodology which can be applied to studies of different disorders.

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“…NFAT1-deficient mice older than 16 months spontaneously develop B cell neoplasms with features of anaplastic and/or plasmablastic plasmacytomas. 58 However, the molecular mechanisms for preferential formation of B cell malignancies in age-associated NFAT1-deficient mice were not elucidated. Regarding the role of NFAT1 in other systems, it has been shown that lack of NFAT1 induces neoplastic transformation of cartilage cells and increased susceptibility to chemically-induced sarcoma formation in mouse models.…”

Section: Discussionmentioning

confidence: 99%

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

et al. 2016

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The NFAT family of transcription factors has been primarily related to T cell development, activation, and differentiation. Further studies have shown that these ubiquitous proteins are observed in many cell types inside and outside the immune system, and are involved in several biological processes, including tumor growth, angiogenesis, and invasiveness. However, the specific role of the NFAT1 family member in naive B cell proliferation remains elusive. Here, we demonstrate that NFAT1 transcription factor controls Cyclin E expression, cell proliferation, and tumor growth in vivo. Specifically, we show that inducible expression of NFAT1 inhibits cell cycle progression, reduces colony formation, and controls tumor growth in nude mice. We also demonstrate that NFAT1-deficient naive B lymphocytes show a hyperproliferative phenotype and high levels of Cyclin E1 and E2 upon BCR stimulation when compared to wild-type B lymphocytes. NFAT1 transcription factor directly regulates Cyclin E expression in B cells, inhibiting the G1/S cell cycle phase transition. Bioinformatics analysis indicates that low levels of NFAT1 correlate with high expression of Cyclin E1 in different human cancers, including Diffuse Large B-cell Lymphomas (DLBCL). Together, our results demonstrate a repressor role for NFAT1 in cell cycle progression and Cyclin E expression in B lymphocytes, and suggest a potential function for NFAT1 protein in B cell malignancies.

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Nfatc2 and Tob1 Have Non-Overlapping Function in T Cell Negative Regulation and Tumorigenesis

Cited by 14 publications

References 44 publications

Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player

Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player

Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: a systems bioinformatics approach

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

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