The GTPase RAB20 is a HIF target with mitochondrial localization mediating apoptosis in hypoxia

Hackenbeck, Thomas; Huber, Regina; Schietke, Ruth; Knaup, Karl X.; Monti, Juliana; Wu, Xiaoqing; Klanke, Bernd; Frey, Benjamin; Gaipl, Udo S.; Wullich, Bernd; Ferbus, Didier; Goubin, Gérard; Warnecke, Christina; Eckardt, Kai‐Uwe; Wiesener, Michael S.

doi:10.1016/j.bbamcr.2010.10.019

Cited by 27 publications

(30 citation statements)

References 48 publications

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“…We show that Rab20 is expressed in skeletal muscle, and the expression is induced by HIF-1a. In accordance, Hackenbeck et al (15) reported that RAB20 is a direct target of HIF-1a. The fact that RAB20 expression is substantially upregulated by exercise in skeletal muscle underpins the biological significance.…”

Section: Discussionsupporting

confidence: 68%

Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1α Pathway

et al. 2017

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Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before the onset of the disease. It is well accepted that physical activity improves glycemic control, but the knowledge on underlying mechanisms mediating the beneficial effects remains incomplete. Exercise is accompanied by a decrease in intramuscular oxygen levels, resulting in induction of HIF-1α. HIF-1α is a master regulator of gene expression and might play an important role in skeletal muscle function and metabolism. Here we show that HIF-1α is important for glucose metabolism and insulin action in skeletal muscle. By using a genome-wide gene expression profiling approach, we identified and as two novel exercise/HIF-1α-regulated genes in skeletal muscle. Loss of Rab20 impairs insulin-stimulated glucose uptake in human and mouse skeletal muscle by blocking the translocation of GLUT4 to the cell surface. In addition, exercise/HIF-1α downregulates the expression of , a well-known negative regulator of insulin action. In conclusion, we are the first to demonstrate that HIF-1α is a key regulator of glucose metabolism in skeletal muscle by directly controlling the transcription of and These results hint toward a novel function of HIF-1α as a potential pharmacological target to improve skeletal muscle insulin sensitivity.

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Section: Discussionsupporting

confidence: 68%

Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1α Pathway

et al. 2017

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“…To test antibody specificity in immunoblot assay, HeLa cells were transiently transfected with hSPAG4-GFP or a previously published HIF-target Rab20-GFP [38] as control. Western blot analysis shows both proteins being detected by anti-GFP antibody and specific signal detection of hSPAG4 by our hSPAG4 polyclonal antibody (Supplemental Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro

Knaup¹,

Monti²,

Hackenbeck³

et al. 2013

Molecular Carcinogenesis

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Hypoxia leads to the upregulation of a variety of genes mediated largely via the hypoxia inducible transcription factor (HIF). Prominent HIF-regulated target genes such as the vascular endothelial growth factor (VEGF), the glucose transporter 1 (Glut-1), or erythropoietin (EPO) help to assure survival of cells and organisms in a low oxygenated environment. Here, we are the first to report the hypoxic regulation of the sperm associated antigen 4 (SPAG4). SPAG4 is a member of the cancer testis (CT) gene family and to date little is known about its physiological function or its involvement in tumor biology. A number of CT family candidate genes are therefore currently being investigated as potential cancer markers, due to their predominant testicular expression pattern. We analyzed RNA and protein expression by RNAse protection assay, immunofluorescent as well as immunohistological stainings. To evaluate the influence of SPAG4 on migration and invasion capabilities, siRNA knockdown as well as transient overexpression was performed prior to scratch or invasion assay analysis. The hypoxic regulation of SPAG4 is clearly mediated in a HIF-1 and VHL dependent manner. We furthermore show upregulation of SPAG4 expression in human renal clear cell carcinoma (RCC) and co-localization within the nucleolus in physiological human testis tissue. SPAG4 knockdown reduces the invasion capability of RCC cells in vitro and overexpression leads to enhancement of tumor cell migration. Together, SPAG4 could possibly play a role in the invasion capability and growth of renal tumors and could represent an interesting target for clinical intervention.

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“…RAB20 (Ras-related in brain 20) is a member of the Rab family of small GTP-binding proteins and localizes to the mitochondria or the vicinity of the Golgi apparatus [26], [27]. RAB20 gene transcription is up-regulated by Hypoxia-inducible transcription factor (HIF) under hypoxia [27]. The RAB20 promoter has a hypoxia responsive element (HRE) 7-bp upstream from the transcriptional start site (TSS) in human cells.…”

Section: Discussionmentioning

confidence: 99%

TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

et al. 2013

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TdIF1 was originally identified as a protein that directly binds to DNA polymerase TdT. TdIF1 is also thought to function in transcription regulation, because it binds directly to the transcriptional factor TReP-132, and to histone deacetylases HDAC1 and HDAC2. Here we show that TdIF1 recognizes a specific DNA sequence and regulates gene transcription. By constructing TdIF1 mutants, we identify amino acid residues essential for its interaction with DNA. An in vitro DNA selection assay, SELEX, reveals that TdIF1 preferentially binds to the sequence 5′-GNTGCATG-3′ following an AT-tract, through its Helix-Turn-Helix and AT-hook motifs. We show that four repeats of this recognition sequence allow TdIF1 to regulate gene transcription in a plasmid-based luciferase reporter assay. We demonstrate that TdIF1 associates with the RAB20 promoter, and RAB20 gene transcription is reduced in TdIF1-knocked-down cells, suggesting that TdIF1 stimulates RAB20 gene transcription.

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The GTPase RAB20 is a HIF target with mitochondrial localization mediating apoptosis in hypoxia

Cited by 27 publications

References 48 publications

Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1α Pathway

Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1α Pathway

Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro

TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

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