scholarly journals A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene.

1996 ◽  
Vol 16 (5) ◽  
pp. 2183-2194 ◽  
Author(s):  
J Tsukada ◽  
W R Waterman ◽  
Y Koyama ◽  
A C Webb ◽  
P E Auron
Keyword(s):  
Dna Binding ◽  
Signaling Pathway ◽  
Tyrosine Kinases ◽  
Interleukin 1 ◽  
Binding Specificity ◽  
Binding Activity ◽  
Gamma Interferon ◽  
Dna Binding Activity ◽  
Dna Binding Specificity ◽  
Activation Site

Binding of many cytokines to their cognate receptors immediately activates Jak tyrosine kinases and their substrates, STAT (signal transducers and activators of transcription) DNA-binding proteins. The DNA binding targets of STATs are sequence elements related to the archetypal gamma interferon activation site, GAS. However, association of interleukin 1 (IL-1) with Jak-STAT signaling has remained unresolved. We now report an element termed LILRE (lipopolysaccharide [LPS] and IL-1-responsive element) in the human prointerleukin 1beta gene (IL1B) which can be immediately induced by either lipopolysaccharide (LPS) or IL-1 protein to bind a tyrosine-phosphorylated protein. This LPS- and IL-1-induced factor (LIL factor) is recognized by an antibody raised against the N terminus of Stat1, but not by those specific for either the C terminus of Stat1 or any other GAS-binding STAT. Phosphotyrosine (P-Tyr) specifically inhibits formation of the LIL factor-DNA complex, suggesting the importance of P-Tyr for the DNA-binding activity, as has been found for all STAT dimers. Analysis of DNA-binding specificity demonstrates that the LIL factor possesses a novel GAS-like binding activity that contrasts with those of other STATs in a requirement for a G residue at position 8 (TTCCTGAGA). Further investigation has revealed that IL-6, but neither IL-4 nor gamma interferon, activates the LIL factor. Thus, the existence of such a STAT-like factor (LIL-Stat) relates the LPS and IL-1 signaling pathway to other cytokine receptor signaling pathways via the activation of STATs. Moreover, the unique DNA-binding specificity and antigenicity of this factor suggest that LPS, IL-1, and IL-6 may use a common signaling pathway.

scholarly journals NAD+ Modulates p53 DNA Binding Specificity and Function

2004 ◽  
Vol 24 (22) ◽  
pp. 9958-9967 ◽  
Author(s):  
Kevin G. McLure ◽  
Masatoshi Takagi ◽  
Michael B. Kastan
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Binding Specificity ◽  
Binding Activity ◽  
Vitamin B ◽  
Cancer Therapies ◽  
Dna Binding Activity ◽  
Dna Binding Specificity

ABSTRACT DNA damage induces p53 DNA binding activity, which affects tumorigenesis, tumor responses to therapies, and the toxicities of cancer therapies (B. Vogelstein, D. Lane, and A. J. Levine, Nature 408:307-310, 2000; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Both transcriptional and transcription-independent activities of p53 contribute to DNA damage-induced cell cycle arrest, apoptosis, and aneuploidy prevention (M. B. Kastan et al., Cell 71:587-597, 1992; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Small-molecule manipulation of p53 DNA binding activity has been an elusive goal, but here we show that NAD+ binds to p53 tetramers, induces a conformational change, and modulates p53 DNA binding specificity in vitro. Niacinamide (vitamin B3) increases the rate of intracellular NAD+ synthesis, alters radiation-induced p53 DNA binding specificity, and modulates activation of a subset of p53 transcriptional targets. These effects are likely due to a direct effect of NAD+ on p53, as a molecule structurally related to part of NAD+, TDP, also inhibits p53 DNA binding, and the TDP precursor, thiamine (vitamin B1), inhibits intracellular p53 activity. Niacinamide and thiamine affect two p53-regulated cellular responses to ionizing radiation: rereplication and apoptosis. Thus, niacinamide and thiamine form a novel basis for the development of small molecules that affect p53 function in vivo, and these results suggest that changes in cellular energy metabolism may regulate p53.

TaNAC69 from the NAC superfamily of transcription factors is up-regulated by abiotic stresses in wheat and recognises two consensus DNA-binding sequences

2006 ◽  
Vol 33 (1) ◽  
pp. 43 ◽  
Author(s):  
Gang-Ping Xue ◽  
Neil I. Bower ◽  
C. Lynne McIntyre ◽  
George A. Riding ◽  
Kemal Kazan ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Specificity ◽  
Binding Activity ◽  
Base Substitution ◽  
Nac Domain ◽  
Sequence Identity ◽  
Dna Binding Activity ◽  
Physiological Processes ◽  
Dna Binding Specificity

NAC proteins are one of the largest families of plant transcription factors and have recently been implicated in diverse physiological processes. To elucidate their role in gene regulation, we determined the DNA-binding specificity of a drought- and cold-inducible NAC protein, TaNAC69 from wheat, and analysed its homologues from other species. Two consensus DNA-binding sequences (spanning 23–24 bp) of TaNAC69 were identified through binding site selection and both consisted of two half sites. Comprehensive data on the DNA-binding specificity of TaNAC69 were generated through extensive base substitution mutagenesis. TaNAC69 and its homologue in Arabidopsis, NAP, sharing 75% sequence identity in the NAC domain, exhibited similar DNA-binding specificity. TaNAC69 was able to homodimerise through its NAC domain. The NAC domain consists of five conserved subdomains. Subdomain mutation showed that a loss or reduction in TaNAC69 dimerisation capacity was accompanied with abolition or decrease in its DNA-binding activity. These data suggest that all subdomains are necessary to maintain a functional NAC domain structure required for interaction with DNA and dimerisation.

scholarly journals On exploring effects of coevolving residues on DNA binding specificity of transcription factors

2021 ◽  
Author(s):  
Yizhao Luan ◽  
Zhi Xie
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Specificity ◽  
Binding Activity ◽  
Dna Interactions ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Dna Binding Activity ◽  
Dna Binding Specificity ◽  
The Stability

Transcription factors (TFs) regulate gene expression by specifically binding to DNA targets. Many factors have been revealed to influence TF-DNA binding specificity. Coevolution of residues in proteins occurs due to a common evolutionary history. However, it is unclear how coevolving residues in TFs contribute to DNA binding specificity. Here, we systematically analyzed TF-DNA interactions from high-throughput experiments for seven TF families, including Homeobox, HLH, bZIP_1, Ets, HMG_box, zf-C4 and Zn_clus TFs. Based on TF-DNA interactions, we detected TF subclass determining sites (TSDSs) defining the heterogeneity of DNA binding preference for each TF family. We showed that the TSDSs were more likely to be coevolving with TSDSs than with non-TSDSs, particularly for Homeobox, HLH, Ets, bZIP_1 and HMG_box TF families. Mutation of the highly coevolving residues could significantly reduce the stability of TF-DNA complex. The distant residues from the DNA interface also contributed to TF-DNA binding activity. Overall, our study gave evidence of the functional importance of coevolved residues in refining transcriptional regulation and provided clues to the application of engineered DNA-binding domains and protein.

Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy

2001 ◽  
Vol 281 (6) ◽  
pp. R2048-R2058 ◽  
Author(s):  
Abram M. Madiehe ◽  
Ling Lin ◽  
Christy White ◽  
H. Doug Braymer ◽  
George A. Bray ◽  
...  
Keyword(s):  
Dna Binding ◽  
Signaling Pathway ◽  
Leptin Receptor ◽  
Binding Activity ◽  
Janus Kinase ◽  
Adrenal Steroids ◽  
Western Blots ◽  
Protein Levels ◽  
Dna Binding Activity ◽  
Stat Signaling

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 μg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.

scholarly journals Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1760-1764 ◽  
Author(s):  
SS Tian ◽  
P Lamb ◽  
HM Seidel ◽  
RB Stein ◽  
J Rosen
Keyword(s):  
Dna Binding ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Signal Transduction Pathway ◽  
Binding Activity ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Dna Binding Activity ◽  
Dna Binding Complexes ◽  
Stimulating Factor

Abstract Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G- CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.

scholarly journals NF-kappa B p100 (Lyt-10) is a component of H2TF1 and can function as an I kappa B-like molecule.

1993 ◽  
Vol 13 (10) ◽  
pp. 6089-6101 ◽  
Author(s):  
R I Scheinman ◽  
A A Beg ◽  
A S Baldwin
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Phorbol Esters ◽  
Interleukin 1 ◽  
Binding Activity ◽  
Proteolytic Processing ◽  
Cellular Growth ◽  
Nf Kappa B ◽  
Dna Binding Activity ◽  
Multiple Copies

NF-kappa B is an important transcription factor regulating expression of genes involved in immune function, inflammation, and cellular growth control. NF-kappa B activity is induced by numerous stimuli, such as phorbol esters, B- and T-cell mitogens, the cytokines tumor necrosis factor and interleukin-1, and serum growth factors. The standard model for the induction of NF-kappa B activity involves the release of the transcription factor from a cytoplasmic inhibitor termed I kappa B, allowing translocation of NF-kappa B to the nucleus. I kappa B contains multiple copies of the so-called ankyrin repeat, which are apparently necessary for its function. Subunits comprising NF-kappa B and related binding activities are members of the Rel multigene family. Two such subunits, p50 and p52 (also called p50B), are proteolytically processed from precursors of 105 kDa (also called p105 and NFKB1) and 100 kDa (also called p100, NFKB2, and Lyt-10), respectively. Both contain N-terminal Rel-homologous domains as well as multiple copies of C-terminal ankyrin repeats. We show here that NF-kappa B p100 is a component of the previously identified DNA-binding activity H2TF1. In addition, we show that p100 is localized in the cytoplasm in HeLa cells, where it is associated with c-Rel, p50, or p65 (RelA). In transient-transfection assays, p100 represses the ability of NF-kappa B p65 to activate a kappa B-containing reporter construct. Transfection of p100 also results in a loss of nuclear p65 DNA binding to a kappa B probe, as measured by an electrophoretic mobility shift assay, and a loss of nuclear p65 immunoreactivity, as measured by immunoblotting. This loss of nuclear p65 is paralleled by a gain of p65 DNA-binding activity and immunoreactivity in the cytoplasm. We interpret these data as demonstrating that p100 functions as an I kappa B-like molecule to sequester Rel family members in the cytoplasm. Proteolytic processing of p100 to the activator p52 is predicted to generate several new forms of Rel family heterodimers and therefore represents a form of regulation of NF-kappa B activity distinct from the classic I kappa B pathway.

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