AKNA: Another AT-hook transcription factor “hooking-up” with inflammation

Moliterno, Alison R.; Resar, Linda M.S.

doi:10.1038/cr.2011.96

Cited by 21 publications

(14 citation statements)

References 16 publications

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“…AKNA promotes Cd40 expression suggesting a correlation between low expression of Akna and Cd40 in cPLA 2 α +/+ RPM [49]. AKNA functions in inflammation and cancer [50]. There was also a correlation with the lower expression of genes for guanylate binding proteins (Gbp) and Tnfα in cPLA 2 α +/+ RPM and their transcriptional regulator Irf1 [51].…”

Section: Resultsmentioning

confidence: 99%

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

et al. 2013

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The role of Group IVA cytosolic phospholipase A2 (cPLA2α) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2α releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFα was lower in C. albicans-stimulated cPLA2α+/+ than cPLA2α-/- macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2α+/+ than cPLA2α-/- macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2α+/+ and cPLA2α-/- macrophages (3 h) was compared by microarray. cPLA2α+/+ macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2α-/- macrophages (≥2-fold, p<0.05). Several pro-inflammatory genes were expressed at lower levels (Tnfα, Cx3cl1, Cd40, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna, Ifnγ, several IFNγ-inducible GTPases). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2α+/+ macrophages. Representative genes expressed lower in cPLA2α+/+ macrophages (Tnfα, Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2α, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation.

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Section: Resultsmentioning

confidence: 99%

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

et al. 2013

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“…All HMG proteins share an acidic, carboxyl terminus and associate with chromatin, but are distinguished by unique functional domains that confer distinct DNA binding motifs and biologic activities [21]. The HMGA family is defined by the AT-hook DNA binding domains [13–30], which mediate binding to nuclear chromatin at AT-rich regions in the minor groove, where HMGA1 proteins bend DNA to allow other transcription factors to bind [13–31]. Prior studies also show that HMGA1 proteins bind to mitochondrial DNA at AT-rich regions [32, 33; reviewed in 34].…”

Section: Introductionmentioning

confidence: 99%

The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development

Sumter¹,

Xian²,

Huso³

et al. 2016

CMM

103

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Background & Objectives Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 “transcriptome” is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer’s disease and type-2 diabetes. Conclusion Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.

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“…8 In addition, the generation of an akna knockout animal model showed that, in its absence, the expression of inflammatory cytokines (interferon-γ, and interleukin-1β), neutrophil-specific chemoattractants (NGP, CRAMP and S100A9) and a neutrophil collagenase (matrix metalloproteinase-9) is enhanced, which proves the implication of this gene in the negative regulation of inflammatory processes. 11,12 Even though akna is located in a common fragile site linked to loss-of-function mutations (FRA9E) associated with neoplastic diseases, 9,[13][14][15][16] the only evidence of its direct association with CC is the one reported by our group in 2010. 17 In that work, we found a significant, high magnitude association (odds ratio (OR) = 3.66, 95% confidence interval (CI) = 1.…”

Section: Introductionmentioning

confidence: 85%

Cervical cancer-associated promoter polymorphism affects akna expression levels

et al. 2014

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Cervical cancer (CC) is responsible for >260,000 deaths worldwide each year. Efforts are being focused on identifying genetic susceptibility factors, especially in genes related to the immune response. Akna has been proposed to be one of them, but data regarding its functional role in the disease is scarce. Supporting the notion of akna as a CC susceptibility gene, we found two polymorphisms associated with squamous intraepithelial lesion (SIL) and CC; moreover, we identified an association between high akna expression levels and CC and SIL, but its direction differs in each disease stage. To show the potential existence of a cis-acting polymorphism, we assessed akna allelic expression imbalance for the alleles of the -1372C>A polymorphism. We found that, regardless of the study group, the number of transcripts derived from the A allele was significantly higher than those from the C allele. Our results support the hypothesis that akna is a CC susceptibility genetic factor and suggest that akna transcriptional regulation has a role in the disease. We anticipate our study to be a starting point for in vitro evaluation of akna transcriptional regulation and for the identification of transcription factors and cis-elements regulating AKNA function that are involved in carcinogenesis.

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AKNA: Another AT-hook transcription factor “hooking-up” with inflammation

Cited by 21 publications

References 16 publications

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development

Cervical cancer-associated promoter polymorphism affects akna expression levels

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