Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue

Eldershaw, Suzy; Sansom, David M.; Narendran, Parth

doi:10.1111/j.1365-2249.2010.04316.x

Cited by 48 publications

(30 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The coordinated overexpression of KRT17, STAT1, and ICAM1 in OSCC is consistent with findings in previous studies [20,24,29,32,33]. Close correlations between KRT17, STAT1, and ICAM1 expression in epithelial cells have been demonstrated in previous studies.…”

Section: Discussionsupporting

confidence: 92%

“…Although accumulating evidence suggests that AIRE is expressed in extrathymic tissues, there are remarkable discrepancies across studies, depending on the techniques used. AIRE mRNA has been detected by RT-PCR in lymph nodes, tonsils, gut-associated lymphoid tissues, spleen, liver, testes, and ovaries [29]. Thymic AIRE mRNA expression is the highest and could also be detected by northern blotting [30,31].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression

Sakamoto

Nguyen

Sawangarun

et al. 2019

Preprint

View full text Add to dashboard Cite

Autoimmune regulator (AIRE) is a transcriptional regulator that is primarily expressed in medullary epithelial cells, where it induces tissue-specific antigen expression. Under pathological conditions, AIRE expression is induced in epidermal cells and promotes skin tumor development in association with stress-responsive keratin KRT17. This study aimed to clarify the role of AIRE in the pathogenesis of oral squamous cell carcinoma (OSCC). AIRE expression was evaluated in seven OSCC cell lines and in OSCC tissue specimens. Transient or constitutive expression of AIRE in 293A cells induced KRT17 expression. cDNA microarray analysis of 293A cells stably expressing AIRE revealed that STAT1 and ICAM1 were significantly upregulated by AIRE. Expression of KRT17, STAT1, ICAM1, MMP9, CXCL10, and CXCL11 was elevated in 293A cells stably expressing AIRE, and conversely, was decreased in AIRE-knockout HSC3 OSCC cells when compared to the respective controls. Upregulation of KRT17, STAT1, and ICAM in OSCC cells was confirmed in tissue specimens by immunohistochemistry. We provide evidence that AIRE exerts transcriptional control in cooperation with ETS1. Expression of STAT1, ICAM1, CXCL10, and MMP9 was increased in 293A cells upon Ets1 transfection, and coexpression of AIRE resulted in enhanced expression of STAT1. AIRE coprecipitated with ETS1 in a modified immunoprecipitation assay using formaldehyde crosslinking. Chromatin immunoprecipitation and quantitative PCR analysis revealed that promoter fragments of STAT1, ICAM1, CXCL10, and MMP9 were enriched in the AIRE precipitates. In oral cancer cells, ETS1 was diffusely located in the nucleus and partially overlapped with dot-like AIRE 4 accumulation sites. Nuclear translocation of AIRE was promoted by cotransfection with Ets1. These results indicate that AIRE is induced in OSCC and supports cancer-related gene expression in cooperation with ETS1. This is a novel function of AIRE in extrathymic tissues under the pathological condition.7 keratinocytes [8][9][10][11]. In the mouse epidermis, Aire is induced by inflammatory or tumorigenic stimuli concurrently with Krt17 and stimulates the transcription of several chemokine genes, such as Cxcl10and Cxcl11, and a gene encoding matrix-degrading enzyme, Mmp9, in keratinocytes [6]. The onset of genetically induced skin tumor is delayed in Aire-knockout mice, which mimic the phenotype of Krt17-knockout mice [6]. These results suggest a novel role of AIRE in extrathymic epithelial tissues under pathological conditions; however, the significance of AIRE in other cancers remains to be elucidated.The above findings inspired us to evaluate whether AIRE participates in the pathogenesis of OSCC. To this end, we first assessed the expression of AIRE in OSCC. Then, we explored the role of AIRE in the regulation of KRT17 and other genes associated with OSCC development. Materials and Methods Chemically induced mouse model of tongue and esophageal cancerCD-1 mice were obtained from Sankyo Labo Service Co. (Tokyo, Japan) and were housed in groups ...

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression

Sakamoto

Nguyen

Sawangarun

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…AIRE mRNA has been detected in lymph node, while whether it can be detected in peripheral blood mononuclear cells (PBMCs) has still not been reached an agreement [21]. Thus, to further confirm our results, RT-PCR analysis of total RNA extracted from lymph node needle biopsy of a heterozygous carrier (III-1; G/A) and a healthy control (IV-4; G/G) was performed with the same primers of the minigene analysis.…”

Section: Resultsmentioning

confidence: 99%

A Functional Alternative Splicing Mutation in AIRE Gene Causes Autoimmune Polyendocrine Syndrome Type 1

Zhang

Liu

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease. Loss-of-function mutations of the autoimmune regulator (AIRE) gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser) in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203) containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.

show abstract

“…This is typically followed by hypoparathyroidism, often in the early childhood years, and/or Addison’s disease, predominately in teens or young adults (4, 5). The syndrome is most prevalent in Finnish, Italian, Sardinian, and Iranian Jewish populations (6–8). …”

Section: Discussionmentioning

confidence: 99%

Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient

Huibregtse¹,

Wolfgram

Winer

et al. 2014

Journal of Pediatric Endocrinology and Metabolism

View full text Add to dashboard Cite

Autoimmune polyglandular syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autoimmune disease that results from autosomal recessive mutations of the human autoimmune regulatory (AIRE) gene. We present the case of a 17-year-old North American girl of primarily Norwegian descent with a novel AIRE gene mutation causing APS-1. In addition to the classic triad of chronic candidiasis, hypoparathyoidism and autoimmune adrenocortical insufficiency, she also has vitiligo, intestinal malabsorption, autoimmune hepatitis, autoimmune hypothyroidism, myositis, myalgias, chronic fatigue, and failure to thrive. Genetic testing revealed heterozygosity for c.20_115de196 and c.967_979del13 mutations in the AIRE gene. The AIRE gene c.20_115de196 mutation has not been previously reported.

show abstract

Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue

Cited by 48 publications

References 80 publications

AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression

AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression

A Functional Alternative Splicing Mutation in AIRE Gene Causes Autoimmune Polyendocrine Syndrome Type 1

Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient

Contact Info

Product

Resources

About