The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis

Ranger, Ann; Gerstenfeld, Louis C.; Wang, Jinxi; Kon, Tamiyo; Bae, Hyunsu; Gravallese, Ellen M.; Glimcher, Melvin J.; Glimcher, Laurie H.

doi:10.1084/jem.191.1.9

Cited by 183 publications

(166 citation statements)

References 79 publications

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“…In the adult heart, calcineurin signaling has a central role in cardiac hypertrophy (Bueno et al, 2002b). In addition to the heart, calcineurin signal transduction is active during development and adult adaptive responses of skeletal muscle, neurons, and the immune system, and there is emerging evidence for the importance of this signaling pathway in cartilage, skin, and smooth muscle (Baksh and Burakoff, 2000;Olson and Williams, 2000;Ranger et al, 2000;Graef et al, 2001bGraef et al, , 2003Crabtree and Olson, 2002). These initial studies have all been performed using mammalian systems and tissue culture.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin signaling in avian cardiovascular development

Liberatore

Yutzey

2003

Developmental Dynamics

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Experiments were initiated in avian embryos to determine the embryonic expression of calcineurin protein phosphatase isoforms as well as to identify developmental processes affected by inhibition of calcineurin signal transduction. Chicken calcineurin A alpha (CnA␣) and calcineurin A beta (CnA␤) are differentially expressed in the developing cardiovascular system, including primitive heart tube and valve primordia. Inhibition of calcineurin signaling by cyclosporin A (CsA) treatment in ovo resulted in distinct cardiovascular malformations, depending on the timing and localization of treatment. Initial formation of the heart tube was apparently normal in embryos treated with CsA from embryonic day (E)1 to E2, but hallmarks of heart failure were apparent with treatment from E2 to E3. Vascular defects were apparent in whole embryos treated on either day, but local administration of CsA directly to the forming vessels on E2 did not inhibit blood vessel formation. This observation supports an indirect effect of calcineurin inhibition on angiogenic remodeling as a result of compromised heart development. Together these studies are consistent with multiple roles for calcineurin signaling in the developing cardiovascular system.

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Section: Discussionmentioning

confidence: 99%

Calcineurin signaling in avian cardiovascular development

Liberatore

Yutzey

2003

Developmental Dynamics

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“…These bone marrow stem cells are pluripotent and capable of differentiating into several lineages such as chondrocytes, myocytes, and adipocytes in addition to osteoblasts (3). Interestingly, Cn/NFAT signaling has been shown to play a critical role in the lineage decision of stem cells to differentiate into chondrocytes, myocytes, and adipocytes (34,36,37). Indeed, the global deletion of NFATc2 in mice has been shown to increase the expression of chondrocytic-specific genes and chondrogenesis, suggesting that NFATc2 is a negative regulator of chondrocyte growth and differentiation (37).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Cn/NFAT signaling has been shown to play a critical role in the lineage decision of stem cells to differentiate into chondrocytes, myocytes, and adipocytes (34,36,37). Indeed, the global deletion of NFATc2 in mice has been shown to increase the expression of chondrocytic-specific genes and chondrogenesis, suggesting that NFATc2 is a negative regulator of chondrocyte growth and differentiation (37). Global NFATc2/c4 double knock-out mice exhibit defects in fat accumulation and reduced adiposity, suggesting that NFAT signaling is positive regulator of adipogenesis (38).…”

Section: Discussionmentioning

confidence: 99%

Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption

Yeo

Beck

Thompson

et al. 2007

Journal of Biological Chemistry

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We recently reported that the pharmacological inhibition of calcineurin (Cn) by low concentrations of cyclosporin A increases osteoblast differentiation in vitro and bone mass in vivo. To determine whether Cn exerts direct actions in osteoblasts, we generated mice lacking Cnb1 (Cn regulatory subunit) in osteoblasts (⌬Cnb1 OB ) using Cre-mediated recombination methods. Transgenic mice expressing Cre recombinase, driven by the human osteocalcin promoter, were crossed with homozygous mice that express loxP-flanked Cnb1 (Cnb1 f/f ). Microcomputed tomography analysis of tibiae at 3 months showed that ⌬Cnb1 OB mice had dramatic increases in bone mass compared with controls. Histomorphometric analyses showed significant increases in mineral apposition rate (67%), bone volume (32%), trabecular thickness (29%), and osteoblast numbers (68%) as well as a 40% decrease in osteoclast numbers as compared with the values from control mice. To delete Cnb1 in vitro, primary calvarial osteoblasts, harvested from Cnb1 f/f mice, were infected with adenovirus expressing the Cre recombinase. Cre-expressing osteoblasts had a complete inhibition of Cnb1 protein levels but differentiated and mineralized more rapidly than control, green fluorescent protein-expressing cells. Deletion of Cnb1 increased expression of osteoprotegerin and decreased expression of RANKL. Co-culturing Cnb1-deficient osteoblasts with wild type osteoclasts demonstrated that osteoblasts lacking Cnb1 failed to support osteoclast differentiation in vitro. Taken together, our findings demonstrate that the inhibition of Cnb1 in osteoblasts increases bone mass by directly increasing osteoblast differentiation and indirectly decreasing osteoclastogenesis.Bone is a highly dynamic structure that is constantly renewing through a process called remodeling (1). This process is critical for maintaining healthy bones and is mainly controlled by the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The presence of these two opposing cell types with contrasting activities in close proximity requires tight regulation to maintain healthy and strong bones. Bone resorption is attained by the action of osteoclasts, which are specialized macrophages whose differentiation is primarily regulated by receptor activator of NF B ligand (RANKL) 2 and osteoprotegerin (OPG) (2). Osteoblasts originate from multipotent mesenchymal progenitors that replicate as undifferentiated cells but have the potential to differentiate into different lineages of mesenchymal tissues including bone, cartilage, fat, muscle, and marrow stroma (3, 4). Osteoblasts control bone formation not only by synthesizing bone matrix proteins and regulating mineralization but also by orchestrating the process of bone resorption through the modulation of RANKL and OPG expression (2, 4).We have recently shown that the pharmacologic inhibition of calcineurin (Cn) by low concentrations of cyclosporin A (CsA) increases osteoblast differentiation and bone formation (5). We also demonstrated that this response was...

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“…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. 46,59 Also, constitutively active NFAT1 (CA-NFAT1) was able to antagonize H-RasV12 oncogene-induced transformation of NIH 3T3 fibroblasts. 46 Collectively, these data suggest a tumor suppressor role for NFAT1 in different cell types.…”

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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The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis

Cited by 183 publications

References 79 publications

Calcineurin signaling in avian cardiovascular development

Calcineurin signaling in avian cardiovascular development

Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption

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

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