AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH

Liiv, Ingrid; Haljasorg, Uku; Kisand, Kai; Maslovskaja, Julia; Laan, Martti; Peterson, Pärt

doi:10.1016/j.bbrc.2012.05.057

Cited by 26 publications

(21 citation statements)

References 30 publications

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“…10 Accordingly, loss of AIRE was observed in both human and murine thymomas. 23,24 Other studies indicated a role of AIRE in increasing apoptosis when expressed in thymic and thyroid epithelial models [8][9] , suggesting that overproduction of TSAs rather than induction of an apoptotic program might indirectly induce cellular stress leading to death. Such a role does not conflict with the nature of AIRE as a transcription factor, since it favors a continuous turnover of antigen-presenting mTECs and promote cross-presentation of tissue-specific antigens to developing thymocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Since individual mTECs transcribe TSA genes stochastically to favor a continuous turnover of presented antigen peptides, AIRE supports mTEC apoptosis. [8][9][10] Moreover, AIRE acts in the tolerance process by favoring the development of regulatory T cells. 11,12 Not only is AIRE highly expressed in mTECs, but there is evidence of AIRE expression in murine peripheral lymphoid organs.…”

Section: Introductionmentioning

confidence: 99%

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Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

et al. 2016

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The autoimmune regulator gene (AIRE) plays a fundamental role in tolerance by promoting the expression of tissue-specific antigens in medullary thymic epithelial cells (mTECs). Recently, AIRE expression was detected also in human keratinocytes and in tumors originating in stratified epithelia. Here, we tested whether AIRE is expressed in cancer cells. We analyzed AIRE expression in cancer cases from The Cancer Genome Atlas (TCGA) RNA-seq dataset and we found association with better outcome. AIRE protein expression was verified by immunohistochemistry in a cohort of 39 human breast cancer specimens and its prognostic relevance was confirmed in microarray-based gene expression data set NKI-295 and KM-Plotter. Both in the RNA-seq and gene expression datasets analyzed, AIRE expression was an independent strong prognostic factor for relapse-free survival (RFS), particularly in estrogen receptor-positive tumors. Enrichment of translation-related pathways was observed in AIRE-expressing tumors by Ingenuity Pathway Analysis and a significant increase of cells in G1 phase and activation of caspase cascades was induced by AIRE transfection in breast cancer luminal cell lines, suggesting that AIRE-induced over-translation of proteins lead to cycle arrest and apoptosis. These data are the first to identify AIRE expression in breast cancer and an association with prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

et al. 2016

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“…Proteins involved in most frequent functional events occurring in the thymus, i.e., apoptosis and antigen processing, were major providers of peptides for their presentation by HLA-DR. The apoptosis-related peptides may come from the uptake of apoptotic cells (mostly thymocytes) by APCs (7, 8) or directly from the AutoImmune REgulator (AIRE)-induced mTEC apoptosis (9–11). The remaining source proteins were of high diverse origin, including nuclear and cytosolic proteins, conventionally considered as belonging to the Class I – endogenous pathway.…”

Section: Peptide Repertoire In Thymusmentioning

confidence: 99%

The Repertoires of Peptides Presented by MHC-II in the Thymus and in Peripheral Tissue: A Clue for Autoimmunity?

et al. 2013

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T-cell tolerance to self-antigens is established in the thymus through the recognition by developing thymocytes of self-peptide-MHC complexes and induced and maintained in the periphery. Efficient negative selection of auto-reactive T cells in the thymus is dependent on the in situ expression of both ubiquitous and tissue-restricted self-antigens and on the presentation of derived peptides. Weak or inadequate intrathymic expression of self-antigens increases the risk to generate an autoimmune-prone T-cell repertoire. Indeed, even small changes of self-antigen expression in the thymus affect negative selection and increase the predisposition to autoimmunity. Together with other mechanisms, tolerance is maintained in the peripheral lymphoid organs via the recognition by mature T cells of a similar set of self-peptides in homeostatic conditions. However, non-lymphoid peripheral tissue, where organ-specific autoimmunity takes place, often have differential functional processes that may lead to the generation of epitopes that are absent or non-presented in the thymus. These putative differences between peptides presented by MHC molecules in the thymus and in peripheral tissues might be a major key to the initiation and maintenance of autoimmune conditions.

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“…Their studies suggest that AIRE-positive cells were more likely to undergo spontaneous apoptosis and that they were less resistant to apoptosis inducers. Besides, recent studies have pointed toward a possible role of AIRE in regulating germ cell apoptosis (6) and that it is associated with NO-induced cellular stress in AIRE-expressing cells (46). Caspase 3, executioner caspase has been shown to be upregulated in our proteomics data.…”

Section: Discussionmentioning

confidence: 67%

Autoimmune Regulator (AIRE) Is Expressed in Spermatogenic Cells, and It Altered the Expression of Several Nucleic-Acid-Binding and Cytoskeletal Proteins in Germ Cell 1 Spermatogonial (GC1-spg) Cells

Radhakrishnan

Bhagya

Kumar

et al. 2016

Molecular & Cellular Proteomics

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Autoimmune regulator (AIRE) is a gene associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE is expressed heavily in the thymic epithelial cells and is involved in maintaining selftolerance through regulating the expression of tissuespecific antigens. The testes are the most predominant extrathymic location where a heavy expression of AIRE is reported. Homozygous Aire-deficient male mice were infertile, possibly due to impaired spermatogenesis, deregulated germ cell apoptosis, or autoimmunity. We report that AIRE is expressed in the testes of neonatal, adolescent, and adult mice. AIRE expression was detected in glial cell derived neurotrophic factor receptor alpha (

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AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH

Cited by 26 publications

References 30 publications

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

The Repertoires of Peptides Presented by MHC-II in the Thymus and in Peripheral Tissue: A Clue for Autoimmunity?

Autoimmune Regulator (AIRE) Is Expressed in Spermatogenic Cells, and It Altered the Expression of Several Nucleic-Acid-Binding and Cytoskeletal Proteins in Germ Cell 1 Spermatogonial (GC1-spg) Cells

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