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GSE44925
Mus musculus
16 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF.
Publication Title
Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Treatment
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Protein synthesis belongs to the most energy consuming processes in the cell. Lowering oxygen tension below normal (hypoxia) causes a rapid inhibition of global mRNA translation due to the decreased availability of energy. Interestingly, subsets of mRNAs pursue active translation under such circumstances. In human fibrosarcoma cells (HT1080) exposed to prolonged hypoxia (36 h, 1% oxygen) we observed that transcripts are either increasingly or decreasingly associated with ribosomes localized at the endoplasmic reticulum (ER). In a global setting it turned out that only 31% of transcripts showing elevated total-RNA levels were also increasingly present at the ER in hypoxia. These genes, regulated by its expression as well as its ER-localization, belong to the gene ontologys hypoxia response, glycolysis and HIF-1 transcription factor network supporting the view of active mRNA translation at the ER during hypoxia. Interestingly, a large group of RNAs was found to be unchanged at the expression level, but translocate to the ER in hypoxia. Among these are transcripts encoding translation factors and >180 ncRNAs. In summary, we provide evidence that protein synthesis is favoured at the ER and, thus, partitioning of the transcriptome between cytoplasmic and ER associated ribosomes mediates adaptation of gene expression in hypoxia.
Publication Title
Hypoxia-induced gene expression results from selective mRNA partitioning to the endoplasmic reticulum.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Homeobox genes encode transcription factors regulating basic processes in cell differentiation during embryogenesis and in the adult. Recently, we have reported the NKL-code which describes physiological expression patterns of nine NKL homeobox genes in early hematopoiesis and in lymphopoiesis including main stages of T-, B- and NK-cell development. Aberrant activity of NKL homeobox genes is involved in the generation of hematological malignancies including T-cell leukemia. Here, we searched for deregulated NKL homeobox genes in main entities of T-cell lymphomas comprising peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), hepatospleenic T-cell lymphoma (HSTL), and NK/T-cell lymphoma (NKTL). Our data revealed in all types altogether 19 aberrantly overexpressed genes, demonstrating that deregulated NKL homeobox genes play a significant role in T-cell lymphomas as well. For detailed analyses we focused on NKL homeobox gene MSX1 which is normally expressed in NK-cells and aberrantly activated in T-cell leukemia. This gene was overexpressed in subsets of HSTL patients and HSTL-derived sister cell lines DERL-2 and DERL-7 which served as models to identify mechanisms of deregulation. We performed genomic and expression profiling and whole genome sequencing and revealed mutated and deregulated gene candidates including the fusion gene CD53-PDGFRB exclusively expressed in DERL-2. Subsequent knockdown experiments allowed the construction of an aberrant network involved in MSX1 deregulation containing chromatin factors AUTS2 and H3B/H3.1, PDGF- and BMP-signalling pathways, and homeobox genes NKX2-2 and PITX1. The gene encoding AUTS2 is located at 7q11 and may represent a basic target of the HSTL hallmark aberration i(7q). Our data indicate both oncogenic and tumor suppressor functions of MSX1 in HSTL, reflecting its activity in early lineage differentiation of T- and NK-cells and the presence of NK-cell like characteristics in malignant HSTL cells. In this context, NKL homeobox gene MSX1 may represent a selective target in HSTL tumor evolution. Together, the data highlight an oncogenic role of deregulated NKL homeobox genes in T-cell lymphoma and identified MSX1 as a novel player in HSTL, involved in aberrant NK- and T-cell differentiation.
Publication Title
Deregulated expression of NKL homeobox genes in T-cell lymphomas.
Sample Metadata Fields
Disease, Disease stage, Cell line
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