Expression analysis of nuclear factor of activated T cells (NFAT) during myeloid differentiation of CD34+ cells: regulation of Fas ligand gene expression in megakaryocytes

Kiani, Alexander; Kuithan, Hanna; Kuithan, Friederike; Kyttälä, Satu; Habermann, Ivonne; Temme, Achim; Bornhäuser, Martin; Ehninger, Gerhard

doi:10.1016/j.exphem.2007.02.001

Cited by 27 publications

(49 citation statements)

References 59 publications

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“…This is most likely due to a mild inability of the AV-NFAT1-expressing cell populations to compete with cells in which the hyperactivable protein is not expressed. These findings are consistent with a previous report showing that as hematopoietic stem cells begin to differentiate, expression of all NFAT family members is downregulated (38,39); in contrast, hyperactivable NFAT1 proteins expressed from the R26 locus would not be downregulated, and progenitor cells expressing these proteins, even at low levels, would display inappropriately sustained NFAT activity, potentially conferring a competitive disadvantage on those cell populations. NFAT1 has been shown to repress expression of the G 0 /G 1 checkpoint kinase cyclin-dependent kinase 4 (CDK4) (40).…”

Section: Discussionsupporting

confidence: 81%

Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development

Müller

Sasaki

Stevanović

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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NFAT transcription factors are highly phosphorylated proteins residing in the cytoplasm of resting cells. Upon dephosphorylation by the phosphatase calcineurin, NFAT proteins translocate to the nucleus, where they orchestrate developmental and activation programs in diverse cell types. NFAT is rephosphorylated and inactivated through the concerted action of at least 3 different kinases: CK1, GSK-3, and DYRK. The major docking sites for calcineurin and CK1 are strongly conserved throughout vertebrate evolution, and conversion of either the calcineurin docking site to a high-affinity version or the CK1 docking site to a low-affinity version results in generation of hyperactivable NFAT proteins that are still fully responsive to stimulation. In this study, we generated transgenic mice expressing hyperactivable versions of NFAT1 from the ROSA26 locus. We show that hyperactivable NFAT increases the expression of NFAT-dependent cytokines by differentiated T cells as expected, but exerts unexpected signal-dependent effects during T cell differentiation in the thymus, and is progressively deleterious for the development of B cells from hematopoietic stem cells. Moreover, progressively hyperactivable versions of NFAT1 are increasingly deleterious for embryonic development, particularly when normal embryos are also present in utero. Forced expression of hyperactivable NFAT1 in the developing embryo leads to mosaic expression in many tissues, and the hyperactivable proteins are barely tolerated in organs such as brain, and cardiac and skeletal muscle. Our results highlight the need for balanced Ca/NFAT signaling in hematopoietic stem cells and progenitor cells of the developing embryo, and emphasize the evolutionary importance of kinase and phosphatase docking sites in preventing inappropriate activation of NFAT.T he activities of many signaling proteins and transcription factors are tightly regulated by phosphorylation and dephosphorylation. Protein kinases and phosphatases bind to specific docking sites on these intracellular proteins to allow their activation or inactivation at the appropriate location and time. A well-studied example of a transcription factor regulated in this fashion is nuclear factor of activated T cells (NFAT) (1-3). In resting cells, NFAT proteins are highly phosphorylated and reside in the cytoplasm; upon cell activation, they are dephosphorylated by the calcium/calmodulindependent phosphatase calcineurin and translocate to the nucleus. NFAT transcription factors play a key role in orchestrating diverse developmental programs, including those of the immune, central nervous, cardiovascular, and musculoskeletal systems (4-11). NFAT also is implicated in maintaining the quiescent state of stem cells in the skin (12).NFAT activation is initiated by dephosphorylation of the NFAT regulatory domain, a conserved 300-amino acid region located N-terminal to the DNA-binding domain (Fig. 1A) (2, 13). The phosphorylated residues (serines) in this domain are distributed among several classes of conserved serine...

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Section: Discussionsupporting

confidence: 81%

Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development

Müller

Sasaki

Stevanović

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Our previous studies showed that members of the NFAT family are expressed in hematopoietic progenitor cells and are regulated during myeloid commitment in a lineage-specific manner. 15,16 These results prompted us to investigate the role of NFATc2 in hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 We, therefore, set out to determine whether NFATc2 was necessary for the intrinsic megakaryocytic differentiation potential of hematopoietic progenitor cells, and also extended this question to other NFAT family members. Of note, activation of NFAT proteins strictly requires posttranslational modification (i.e.…”

Section: Reduced Frequency But Preserved Differentiation Potential Ofmentioning

confidence: 99%

“…Our previous studies show that all members of the NFAT family, except for NFATc4, are expressed in CD34 + HSC and that their expression is differentially regulated during the lineage-specific differentiation of myeloid cells. 15,16 For example, while NFATc4 is not expressed in HSC and remains almost undetectable in differentiated neutrophil, eosinophil and erythroid cells, its expression is strongly induced during megakaryocyte differentiation. In contrast, the expression of NFATc2, which is abundantly found in HSC, is rapidly and almost completely suppressed upon their differentiation into neutrophil granulocytes, but is maintained in the megakaryocyte lineage.…”

Section: Introductionmentioning

confidence: 99%

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Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Bauer¹,

Rauner²,

Haase³

et al. 2011

Haematologica

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“…Calcineurin is a calcium-dependent phosphatase which, upon a sustained rise in intracellular calcium, dephosphorylates NFATs, which allows their entry into the nucleus. The two main NFATs expressed in MKs are NFATC1 and NFATC2 [169]. Calcium entry into MKs in response to collagen, for example, has been shown to induce calcineurin/NFATs [170].…”

Section: Nfatmentioning

confidence: 99%

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Tijssen

Moreau

Ghevaert

2016

Molecular and Cellular Biology of Platelet Formation

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It is now common knowledge that specific repertoires of transcription factors (TFs) determine a cell's protein content and thereby its phenotype. The expression of a given TF is not necessarily cell specific, and many TFs play a pivotal role in several different cell types. For example, TAL1, FLI1, RUNX1, ERG and GATA2 are important regulators of stem cells, but also play a vital role in megakaryopoiesis. Although the megakaryocyte (MK) and its closest relative, the red blood cell, share key TFs like GATA1 and NFE2, the bifurcation between the two lineages has been associated with pairs of TFs that act as a toggle switch (such as FLI1 and KLF1). This chapter will summarise the current knowledge of key transcriptional regulators of MK differentiation and how some of these TFs, despite being expressed in several cell types, can impose MK cell identity. Since the discovery of TPO in 1994, our knowledge of MK biology and differentiation has increased exponentially, but we still lack a deep understanding of what triggers the transition from MK growth and maturation to proplatelet formation. We describe how some well-known TFs control the expression of proteins that play a pivotal role in the dramatic cytoplasmic and cytoskeletal events that accompany proplatelet formation. Finally, we show how TFs can be harnessed in a powerful way to produce MKs and, potentially, platelets in vitro for future clinical applications.

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Expression analysis of nuclear factor of activated T cells (NFAT) during myeloid differentiation of CD34+ cells: regulation of Fas ligand gene expression in megakaryocytes

Cited by 27 publications

References 59 publications

Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development

Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development

Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

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