Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA

Chen, Lin; Glover, J. N. Mark; Hogan, Patrick G.; Rao, Anjana; Harrison, Stephen C.

doi:10.1038/32100

Cited by 496 publications

(459 citation statements)

References 44 publications

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“…The transcription also requires coactivators such as activator protein 1, myocyte enhance factor 2 and members of the GATA family. 11 While calcineurin is required to keep NFAT in the nucleus, several serine/threonine kinases such as casein kinase1, glycogen synthase kinase 3b (GSK3b), p38 and C-Jun N-terminal kinase export NFAT from the nucleus by phosphorylating NFAT. Beside phosphorylation, NFAT is also modulated by ubiquitination and sumoylation.…”

Section: Structure Ad Regulation Of Nfatmentioning

confidence: 99%

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

et al. 2017

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Nuclear factor of activated T cells (NFAT) was first identified as a transcription factor about 3 decades ago and was not well studied until the development of immunosuppressant. Numerous studies confirm that calcineurin/NFAT signaling is very important in the development of vasculature and cardiovascular system during embryogenesis and is involved in the development of vascular diseases such as hypertension, atherosclerosis and restenosis. Recent studies demonstrated that NFAT proteins also regulate immune response and vascular cells in the pulmonary microenvironment. In this review, we will discuss how different NFAT isoforms contribute to pulmonary vascular remodeling and potential new therapeutic targets for treating pulmonary arterial hypertension.

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Section: Structure Ad Regulation Of Nfatmentioning

confidence: 99%

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

et al. 2017

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“…This domain is highly phosphorylated on multiple serine residues in resting cells; upon cell activation it is dephosphorylated by the calcium/calmodulin-dependent phosphatase calcineurin, the major upstream regulator of NFAT Beals et al, 1997a;Jain et al, 1993a;Liu et al, 1999;Luo et al, 1996a;Shibasaki et al, 1996). Immediately adjacent to the regulatory domain lies the highly-conserved NFAT DNA binding domain, which is distantly related in its primary sequence but shows a strong structural similarity to the DNA binding domains (Rel homology region) of the Rel/NF-kB family of transcription factors (Chen et al, 1998;Jain et al, 1995a;Nolan, 1994;Zhou et al, 1998). Indeed, as discussed in detail below, NFAT DNA-binding domains cannot only bind cooperatively to DNA with AP-1, but also can form Rel/NF-kB-like dimers on certain types of NFAT-binding DNA elements (Kinoshita et al, 1997;Macian and Rao, 1999;McCa rey et al, 1994).…”

Section: The Nfat Familymentioning

confidence: 99%

Partners in transcription: NFAT and AP-1

2001

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Combinatorial regulation is a powerful mechanism that enables tight control of gene expression, via integration of multiple signaling pathways that induce di erent transcription factors required for enhanceosome assembly. The four calcium-regulated transcription factors of the NFAT family act synergistically with AP-1 (Fos/ Jun) proteins on composite DNA elements which contain adjacent NFAT and AP-1 binding sites, where they form highly stable ternary complexes to regulate the expression of diverse inducible genes. Concomitant induction of NFAT and AP-1 requires concerted activation of two di erent signaling pathways: calcium/calcineurin, which promotes NFAT dephosphorylation, nuclear translocation and activation; and protein kinase C (PKC)/Ras, which promotes the synthesis, phosphorylation and activation of members of the Fos and Jun families of transcription factors. A ®fth member of the NFAT family, NFAT5, controls the cellular response to osmotic stress, by a mechanism that requires dimer formation and is independent of calcineurin or of interaction with AP-1. Pharmacological interference with the NFAT:AP-1 interaction may be useful in selective manipulation of the immune response. Balanced activation of NFAT and AP-1 is known to be required for productive immune responses, but the role of NFAT:AP-1 interactions in other cell types and biological processes remains to be understood. Oncogene (2001) 20, 2476 ± 2489.

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“…X-ray crystallographic models of NFAT and AP1, bound to DNA, have illustrated this clearly. (Chen et al, 1998) The human FIZ1 gene is located near several other genes important to retinal development, such as the CRX gene, on Chromosome-19. This chromosome is particularly rich in Zfproteins.…”

Section: Fiz1 Can Modulate Nrl and Crx-mediated Activation Of Rod Spementioning

confidence: 99%

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

Mali

Zhang

Hoerauf

et al. 2007

Experimental Eye Research

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FIZ1 (Flt-3 Interacting Zinc-finger) interacts and co-purifies with the rod-specific transcription factor NRL (Neural Retina Leucine zipper). We hypothesize that FIZ1 is part of an interface between cell-specific factors, like NRL, and more ubiquitous regulatory networks that vary the absolute expression levels of some rod-specific genes (i.e. Rhodopsin). As part of an ongoing exploration of FIZ1's role in neural retina, in vivo, we have taken the first look at FIZ1 expression in the developing mouse retina during the retinal maturation period. Using the normal C57/B6 mouse as a model, multiple approaches were used including: immunoblotting, immunohistochemistry, and quantitative real-time PCR. Functional implications of FIZ1/NRL interaction, on NRL-and CRX-mediated activation of the Rhodopsin (Rho) and cGMPphosphodiesterase β-subunit gene (PDE6B) promoters, were examined by co-transfection assays. Immunoblot analysis revealed that FIZ1 protein levels were lowest in immature mouse neural retina (P0). FIZ1 concentration increased at least ten-fold as the neural retina matured to the adult state (P21 and later). Immunohistochemical comparison of immature post-natal and mature adult retina revealed increasing FIZ1 protein in photoreceptors, the inner plexiform layer, and the ganglion cell layer. Total retinal Fiz1 mRNA content increased as the neural retina matured. The expected increase in Rho mRNA level was also monitored as a genetic marker of photoreceptor maturation. In transient co-transfection assays of CV1 cells, FIZ1 synergized with NRL to activate transcription from the Rho and PDE6B gene promoters with some differences. In the case of the Rho promoter, FIZ1 synergized when both NRL and CRX were present. With the PDE6B promoter, FIZ1 synergized with NRL alone, and the inclusion of CRX decreased this synergy.Conclusions-These findings support previous evidence that FIZ1 is present in rodphotoreceptors. (Co-immunoprecipitation from nuclear-protein extracts with rod-specific NRL) FIZ1 expression increases in the neural retina during the retinal maturation period. Additionally, in vitro experiments demonstrate that FIZ1 has the potential to significantly increase the NRLmediated activation of photoreceptor-specific promoters. While CRX is not a strong activator of the PDE6B promoter, alone or with NRL, CRX decreased the synergy of NRL with FIZ1.

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Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA

Cited by 496 publications

References 44 publications

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

Partners in transcription: NFAT and AP-1

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

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