STAT4 serine phosphorylation is critical for IL-12-induced IFN-γ production but not for cell proliferation

Morinobu, Akio; Gadina, Massimo; Strober, Warren; Visconti, Roberta; Fornace, Albert J.; Montagna, Cristina; Nishikomori, Ryuta; O’Shea, John J.

doi:10.1073/pnas.182618999

Cited by 193 publications

(144 citation statements)

References 53 publications

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“…STAT4 mediates signals produced by interleukin-12 (IL-12), type I interferon and IL-23, 120 and stimulates IL-12-induced interferon-g production. 121 The rs7574865 SNP of STAT4 was associated with the development of both SLE and RA in Caucasians, 122 and association with SLE was confirmed in two recent GWASs 123,124 and in a Japanese population. 125 A total of 9923 SLE cases and controls in a multiethnic population comprising Europeans, Koreans, Gullahs, African Americans and Hispanics were recently investigated to identify the association between STAT4 and SLE.…”

Section: Irf5mentioning

confidence: 85%

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

Kim

et al. 2009

Genes Immun

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There have been many genetic studies of systemic lupus erythematosus (SLE) in Asia, but the status of SLE in Asia remains unclear. Genes that have been associated with SLE in Caucasians have shown both consistent and inconsistent results in Asians. This prompted us to review studies of SLE-associated genes and compare the degree of consistency according to ethnicity in Asia. We searched PubMed and the national databases in Korea and Japan for SLE genetic studies. A total of 755 articles were found and after applying various exclusion criteria, 442 studies including 17 linkage studies, 2 genome-wide association studies and 423 candidate-gene analyses were reviewed. Nine linkage loci were confirmed to be associated with SLE susceptibility in non-Asians, but the risk locus (16q12) has been identified in only one Asian study. A total of 156 candidate genes were analyzed, of which 92 were studied in Asians. Although there were allelic (HLA-DRB1 and IRF5) or genetic heterogeneity (FCGR gene family), HLA-DRB1, the FCGR gene family, IRF5, STAT4 and MECP2 showed consistent associations with SLE susceptibility across ethnicities. In conclusion, genetic associations often vary with ethnicity, requiring validation in different ethnic groups, and hence future SLE genetic studies will require strong worldwide collaborations.

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Section: Irf5mentioning

confidence: 85%

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

Kim

et al. 2009

Genes Immun

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“…First strand cDNA synthesis and real time PCR were done as described previously (35). Commercial assay reagents for IFN-␥ and glyceraldehyde-3-phosphate dehydrogenase were purchased from Applied Biosystems (Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

Discrete Roles for Histone Acetylation in Human T Helper 1 Cell-specific Gene Expression

Morinobu¹,

Kanno²,

O’Shea

2004

Journal of Biological Chemistry

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To better understand the control of T helper (T H ) 1-expressed genes, we compared and contrasted acetylation and expression for three key genes, IFNG, TBET, and IL18RAP and found them to be distinctly regulated. The TBET and the IFNG genes, but not the IL18RAP gene, showed preferential acetylation of histones H3 and H4 during T H 1 differentiation. Analysis of acetylation of specific histone residues revealed that H3(Lys-9), H4(Lys-8), and H4(Lys-12) were preferentially modified in T H 1 cells, suggesting a possible contribution of acetylation of these residues for induction of these genes. On the other hand, the acetylation of IL18RAP gene occurred both in T H 1 and T H 2 cells with the similar kinetics and on the same residues, demonstrating that selective histone acetylation was not universally the case for all T H 1-expressed genes. Histone H3 acetylation of IFNG and TBET genes occurred with different kinetics, however, and was distinctively regulated by cytokines. Interleukin (IL)-12 and IL-18 enhanced the histone acetylation of the IFNG gene. By contrast, histone acetylation of the TBET gene was markedly suppressed by IL-4, whereas IL-12 and IL-18 had only modest effects suggesting that histone acetylation during T H 1 differentiation is a process that is regulated by various factors at multiple levels. By treating Th2 cells with a histone deacetylase inhibitor, we restored histone acetylation of the IFNG and TBET genes, but it did not fully restore their expression in T H 2 cells, again suggesting that histone acetylation explains one but not all the aspects of T H 1-specific gene expression.

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“…One of the strongest responders to p53 regulation was STAT4, a critical mediator in IL12-induced interferon gamma (IFNg) production. 24,25 Transfection of WT p53, but not the p53null-like SNP P278A in HCT116 (p53 À / À ) cells induced activation of STAT4 mRNA expression (Figure 7a) as well as its corresponding protein (Figure 7b), while knockdown of p53 in HCT116 (p53 þ / þ ) cells significantly diminished STAT4 expression (Figures 7c and d). In addition, treatment with Nutlin 3 or 5FU had similar effects that were also dependent on p53 (Figures 7e and f).…”

Section: Resultsmentioning

confidence: 99%

Mapping the p53 transcriptome universe using p53 natural polymorphs

et al. 2013

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The tumor suppressor p53 has defined roles in varied cellular processes including apoptosis and DNA repair. While conventional genomic approaches have suggested a large number of p53 targets, there is a need for a systematic approach to validate these putative genes. We developed a method to identify and validate p53's transcriptional behavior by utilizing 16 non-synonymous p53 single-nucleotide polymorphism (SNP) variants. Five SNPs located within the DNA-binding domain of p53 were found to be functionally null, whereas the other 11 SNPs were p53WT-like in behavior. By integrating p53 ChIP-seq analysis with transcriptome data from the p53 SNP variants, 592 genes were identified as novel p53 targets. Many of these genes mapped to previously less well-characterized aspects of p53 function, such as cell signalling, metabolism, central nervous system, and immune system. These data provide pivotal insights into the involvement of p53 in diverse pathways of normal physiological processes and open new avenues for investigation of p53 function. Cell Death and Differentiation (2014) 21, 521-532; doi:10.1038/cdd.2013.132; published online 27 September 2013The tumor suppressor p53 acts as a master regulator of cellular stress responses through transcriptionally regulating specific target genes involved in diverse cellular functions including cell cycle arrest, apoptosis, and DNA repair. 1 With the aid of large-scale screening techniques, it has become clear that the scope of p53 functions is much broader than previously thought, 2,3 expanding to cellular and physiological processes such as metabolism 4 and development. 5 To have a better understanding of this important tumor suppressor, we must be able to study the full complexity of its downstream effects and this requires the efficient identification and validation of genes directly regulated by p53. To date, there are fewer than 150 validated p53 target genes 6-8 and at the same time validation studies have been slow, which is a limitation on the progress in this field.In order to be regulated by p53 a gene must possess the appropriate cognate response element (RE) within its regulatory region. However, our previous study has shown that simple sequence motif identification is not sufficient, as the p53RE exhibits variable binding kinetics that are dependent upon the dinucleotide core 'CWWG' combinations. 9 These variables often result in spurious outcomes and hence we are in need of more robust approaches to accurately identify p53 transcriptional networks.Here, we describe an unbiased method to review 135 reported p53 target genes and at the same time identify new p53 targets on a genome-wide scale. We utilized wild-type (WT) p53 together with 16 allelic replicates comprising all reported non-synonymous single-nucleotide polymorphism (SNP) variants of p53. As the transcriptional functions of these 16 SNPs have not been well studied, we first developed a customized luciferase assay with promoter reporter vectors encompassing all combinatorial forms of the dinucleotide ...

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STAT4 serine phosphorylation is critical for IL-12-induced IFN-γ production but not for cell proliferation

Cited by 193 publications

References 53 publications

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

Discrete Roles for Histone Acetylation in Human T Helper 1 Cell-specific Gene Expression

Mapping the p53 transcriptome universe using p53 natural polymorphs

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