Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes

Nowling, Tamara K.; Fulton, Jennifer Dziadyk; Chike-Harris, Katherine; Gilkeson, Gary S.

doi:10.1016/j.molimm.2007.05.018

Cited by 17 publications

(41 citation statements)

References 38 publications

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“…These data suggest that the absence of the CTA domain of Fli1 may interfere with the autoregulation at the transcriptional level, consistent with recent studies that demonstrated involvement of Fli1 in regulating its own expression in lymphocytes (25). We next quantified procollagen type I, III, and V mRNAs using quantitative PCR in the skin tissues of WT and Fli1…”

Section: Resultssupporting

confidence: 87%

Transcription Factor Fli1 Regulates Collagen Fibrillogenesis in Mouse Skin

Asano

Markiewicz

Kubo

et al. 2009

Molecular and Cellular Biology

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Biosynthesis of fibrillar collagen in the skin is precisely regulated to maintain proper tissue homeostasis; however, the molecular mechanisms involved in this process remain largely unknown. Transcription factor Fli1 has been shown to repress collagen synthesis in cultured dermal fibroblasts. This study investigated the role of Fli1 in regulation of collagen biosynthesis in mice skin in vivo using mice with the homozygous deletion of the C-terminal transcriptional activation (CTA) domain of the Fli1 gene (Fli1 ⌬CTA/⌬CTA ). Skin analyses of the Fli1 mutant mice revealed a significant upregulation of fibrillar collagen genes at mRNA level, as well as increased collagen content as measured by acetic acid extraction and hydroxyproline assays. In addition, collagen fibrils contained ultrastructural abnormalities including immature thin fibrils and very thick irregularly shaped fibrils, which correlated with the reduced levels of decorin, fibromodulin, and lumican. Fibroblasts cultured from the skin of Fli1 ⌬CTA/⌬CTA mice maintained elevated synthesis of collagen mRNA and protein. Additional experiments in cultured fibroblasts have revealed that although Fli1 ⌬CTA retains the ability to bind to the collagen promoter in vitro and in vivo, it no longer functions as transcriptional repressor. Together, these results establish Fli1 as a key regulator of the collagen homeostasis in the skin in vivo.Fibril-forming collagens are the major structural components of the dermis responsible for its characteristic strength and resiliency. In the skin collagen fibrils are composed mainly of collagen type I and smaller amounts of collagen types III and V (11). Although collagen type V represents only a minor component of the fibril, it plays a key regulatory role in the process of fibrillogenesis (41). During physiologic remodeling, coordinate synthesis of specific collagen chains is tightly regulated (29), while during fibrosis the fibrillar collagens are produced at increased levels (37). The first critical step in the collagen biosynthetic pathway occurs at the level of transcription. In the past few years, a number of cis-regulatory elements and cognate transcription factors involved in type I collagen gene regulation at the basal level and in response to cytokines have been characterized in in vitro studies (8,13,18,36). Subsequently, several of these response elements, including Sp1 and CBF/nuclear factor 1 binding sites, have been validated in vivo in a transgenic mouse model (34). The in vivo studies have also underscored the complexity of the transcription regulation of the collagen gene, which involves interactions between transcription factor complexes at the proximal promoter and the far upstream enhancer (34).Additional intracellular steps in collagen fibrillogenesis involve collagen folding and trimerization, which take place in the endoplasmic reticulum (3, 23). Prolyl-4 hydroxylase (P4H) and protein disulfide isomerase, which together form a P4H tetramer, catalyze formation of hydroxyproline, a critical step that fa...

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Section: Resultssupporting

confidence: 87%

Transcription Factor Fli1 Regulates Collagen Fibrillogenesis in Mouse Skin

Asano

Markiewicz

Kubo

et al. 2009

Molecular and Cellular Biology

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“…The GA n repeat element in exon 1 is located directly adjacent to Fli1 regulatory elements, specifically, a GATA/EBS dual element known to act as a transcriptional enhancer (5,6,25,26). The GA n repeat element is a known endogenous enhancer of Fli1, and the length of this repeat is inversely correlated with Fli1 promoter activity, i.e., the longer the repeat, the lower the promoter activity and gene expression (25). In B6 mice, the length of the GA n element is 28 GA repeats, and in Bc mice, it is 29 GA repeats.…”

Section: Discussionmentioning

confidence: 99%

“…Any of the three polymorphisms identified may be the cause of the differential disease and gene expression profiles observed between mice carrying the B6 or Bc Fli1 allele; however, of the three polymorphisms observed, the GA n repeat element is of the most interest. Unlike the GT n repeat element and TT deletion event, the GA n repeat element is 100% conserved between mice and humans and is a known endogenous enhancer of Fli1 expression; the length of this repeat is inversely correlated with Fli1 promoter activity (25).…”

Section: Vol 78 2010 Fine Mapping Of Leishmania Major Response Locumentioning

confidence: 99%

Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing

et al. 2010

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Genetic linkage studies of the host response to Leishmania major, the causative agent of cutaneous leishmaniasis, have identified significant genetic complexity in humans and mice. In the mouse model, multiple loci have been implicated in susceptibility to infection, but to date, the genes underlying these loci have not been identified. We now describe the contribution of a novel candidate gene, Fli1, to both L. major resistance and enhanced wound healing. We have previously mapped the L. major response locus, lmr2, to proximal chromosome 9 in a genetic cross between the resistant C57BL/6 strain and the susceptible BALB/c strain. We now show that the presence of the resistant C57BL/6 lmr2 allele in susceptible BALB/c mice confers an enhanced L. major resistance and wound healing phenotype. Fine mapping of the lmr2 locus permitted the localization of the lmr2 quantitative trait locus to a 5-Mb interval comprising 21 genes, of which microarray analysis was able to identify differential expression in 1 geneFli1. Analysis of Fli1 expression in wounded and L. major-infected skin and naïve and infected lymph nodes validated the importance of Fli1 in lesion resolution and wound healing and identified 3 polymorphisms in the Fli1 promoter, among which a GA repeat element may be the important contributor.Cutaneous leishmaniasis (CL) caused by the intracellular protozoan Leishmania major is a parasitic disease transmitted by blood-sucking sandflies. Skin macrophages are infected, and a skin lesion or granuloma develops at the site of infection (31). The severity of human CL varies, with phenotypes ranging from self-healing lesions to persistent lesions lasting years and leading to systemic disease (1). The severity of disease depends on the host's ability to form protective granulomas; in their absence, the parasites spread, resulting in diffuse cutaneous leishmaniasis. Studies of CL in mice have been of immense interest because they allow extensive experimental manipulation and reproduce many of the features of the human disease. To identify factors that modulate lesion resolution in infected individuals, we conducted genetic studies on two inbred mouse strains, C57BL/6 (B6) and BALB/c (Bc), that differ in their susceptibility to L. major. Resistance to L. major, epitomized by B6 mice, is characterized by the rapid healing of skin lesions, while the susceptibility in Bc mice is characterized by lesion chronicity and progression and systemic spread of the parasites.We previously identified three loci (lmr1, lmr2, and lmr3) mediating lesion resolution during L. major infection (28, 29). Mice congenic for all three resistant lmr alleles [strain C.B6-(lmr1, lmr2)] were generated on the susceptible Bc background and were shown to be more resistant to L. major and more able to heal noninfectious wounds than Bc mice, exhibiting a statistically significant tendency toward the phenotype of the donor strain B6. Furthermore, resistance to L. major was independent of T helper cell responses (12,13,30). The conclusions from these stud...

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“…Each real-time reaction was performed in triplicate on the MyiQ Bio-Rad Thermocycler using the iQ SYBR Green Supermix (Bio-Rad), and threshold cycle number for each reaction was determined using the Real-Time iCycler iQ software (Bio-Rad). Relative expression was calculated using the Bio-Rad Gene Expression Macro software as described previously 39 with b-actin as the reference gene. Relative differences between groups are presented as fold change.…”

Section: Gene Expressionmentioning

confidence: 99%

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Nowling

Mather²,

Thiyagarajan

et al. 2015

Journal of the American Society of Nephrology

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Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

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Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes

Cited by 17 publications

References 38 publications

Transcription Factor Fli1 Regulates Collagen Fibrillogenesis in Mouse Skin

Transcription Factor Fli1 Regulates Collagen Fibrillogenesis in Mouse Skin

Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

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