A Similar DNA-binding Motif in NFAT Family Proteins and the Rel Homology Region

Jain, Jugnu; Burgeon, Emmanuel; Badalian, Tina M.; Hogan, Patrick G.; Rao, Anjana

doi:10.1074/jbc.270.8.4138

Cited by 134 publications

(124 citation statements)

References 41 publications

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“…This region included part of the NFAT homology domain and most of the Rel homology domain (residues 216 -618 of NFAT1). The homology stopped abruptly downstream of the minimal DNA binding domain in the Rel homology region (41). The 55-amino acid residue C-terminal peptide encoded by the open reading frame did not show significant homology with any other sequence in the GenBank and EMBL data bases (Fig.…”

Section: Expression Of a Constitutive Nfat Activity In Mouse Brain-mentioning

confidence: 99%

“…The region of homology of NFAT1-D with the other NFAT1 isoforms spans the N-terminal NFAT homology region, which is responsible for transactivation and interaction with calcineurin and contains the phosphorylatable serine residues that modulate NFAT activity through the opposite activities of GSK-3 and calcineurin (3,4,42). It also includes the minimal region of the Rel homology domain required for DNA binding (41). Although NFAT1-A, B, and C differ at their C-termini, the homology among these isoforms extends beyond the Rel homology domain into the C-terminal transactivation domain.…”

Section: Expression Of a Constitutive Nfat Activity In Mouse Brain-mentioning

confidence: 99%

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Identification and Characterization of a Novel Nuclear Factor of Activated T-cells-1 Isoform Expressed in Mouse Brain

Plyte

Boncristiano

Fattori

et al. 2001

Journal of Biological Chemistry

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The nuclear factor of activated T-cells (NFAT) family transcription factors play a key role in the control of cytokine gene expression in T-cells. Although initially identified in T-cells, recent data have unveiled unanticipated roles for NFATs in the development, proliferation, and differentiation of other tissues. Here we report the identification, cDNA cloning, and functional characterization of a new isoform of NFAT1 highly expressed in mouse brain. This isoform, which we named NFAT1-D, is identical to NFAT1 throughout the N-terminal regulatory domain and the portion of the Rel domain which includes the minimal region required for specific binding to DNA and interaction with AP-1. The homology stops sharply upstream of the 3-boundary of the Rel homology domain and is followed by a short unique C-terminal region. NFAT1-D was expressed at high levels in all brain districts and was found as a constitutively active transcription complex. Transfection of a NFAT/luciferase reporter in the neuronal cell line PC12, which also expresses NFAT1-D, showed that these cells expressed a constitutive NFAT activity that was enhanced after nerve growth factor-induced differentiation but was resistant to the immunosuppressant cyclosporin A. NFAT1-D was, however, inducibly activated in a cyclosporin A-sensitive manner when expressed in Tcells, suggesting that the activity of NFAT proteins might be controlled by their specific cellular context. Initially described as a transcriptional complex that bound a T-cell antigen receptor (TCR)1 response element on the interleukin (IL)-2 gene enhancer, nuclear factor of activated T-cells (NFAT) is a family of transcription factors crucially involved in the regulation of cytokine gene expression in T-cells (1). NFAT activity is strongly unregulated after TCR triggering; however, receptor engagement can be bypassed by a combination of phorbol esters and calcium ionophores, which activate protein kinase C and induce a rise in intracellular calcium ions, respectively. This dual requirement reflects the subunit composition of NFAT factors, which includes a cytoplasmic and a nuclear component. In resting cells, NFAT is found as a cytosolic protein phosphorylated on serine residues. After an elevation in intracellular calcium ions, the calmodulin-dependent phosphatase calcineurin is activated and dephosphorylates NFAT, exposing a nuclear localization sequence near the N terminus of NFAT and resulting in its translocation to the nucleus (2-5). This process is exquisitely sensitive to the immunosuppressants cylosporin A (CsA) and FK506, which interact with specific cytosolic receptors and form complexes that bind with high affinity to calcineurin and lock it in an inactive conformation (6 -8). In the nucleus NFAT assembles in cooperative DNAbinding complexes with dimers of the AP-1 family of transcription factors (4, 9). Complementation studies using constitutively active mutants of signaling proteins have shown that the calcium/calcineurin and the Ras/protein kinase C/mitogen-activated protein ki...

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Section: Expression Of a Constitutive Nfat Activity In Mouse Brain-mentioning

confidence: 99%

Section: Expression Of a Constitutive Nfat Activity In Mouse Brain-mentioning

confidence: 99%

Identification and Characterization of a Novel Nuclear Factor of Activated T-cells-1 Isoform Expressed in Mouse Brain

Plyte

Boncristiano

Fattori

et al. 2001

Journal of Biological Chemistry

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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

Self Cite

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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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“…Five members of this family, including NFATc1/2/c, NFATc2/ 1/p, NFATc3/4/x, NFATc4/3, and NFAT5/TonEBP, have been identified in mammals. All members of the NFAT family have highly conserved DNA-binding domain, the Rel homology region (RHR), which confers common DNA-binding specificity (17). Except for NFAT5, NFATc1-c4 are activated upon a rise in intracellular Ca 2ϩ , which stimulates the serine/threonine phosphatase activity of calcineurin (18,19).…”

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confidence: 99%