Dataset Information

Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1? in hypoxic cardiomyocytes.

ABSTRACT: Our previous study suggested that microtubule network alteration affects the process of glycolysis in cardiomyocytes (CMs) via the regulation of hypoxia-inducible factor (HIF)-1? during the early stages of hypoxia. However, little is known regarding the underlying mechanisms of microtubule network alteration-induced changes of HIF-1?. The von Hippel-Lindau tumor suppressor protein (pVHL) has been shown to mediate the ubiquitination of HIF-1? in the nuclear compartment prior to HIF-1? exportation to the cytoplasm, and pVHL dynamic nuclear-cytoplasmic trafficking is indicated to be involved in the process of HIF-1? degradation. In this study, by administering different microtubule-stabilizing and -depolymerizing interventions, we demonstrated that microtubule stabilization promoted pVHL nuclear export and drove the translocation of pVHL to the cytoplasm, while microtubule disruption prevented pVHL nuclear export in hypoxic CMs. Moreover, the ratio between nuclear and cytoplasmic pVHL was associated with HIF-1? regulation. Importantly, microtubule network alteration also affected the subcellular localization of Ran, which was involved in the regulation of pVHL nuclear-cytoplasmic trafficking. The above results suggest that the subcellular translocation of pVHL plays an important role in microtubular structure alteration-induced HIF-1? regulation. Interestingly, Ran is involved in the process of pVHL nuclear-cytoplasmic trafficking following microtubule network alteration in hypoxic CMs.

SUBMITTER: Jiang X

PROVIDER: S-EPMC4361876 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1α in hypoxic cardiomyocytes.

Jiang Xupin X Zhang Dongxia D Zhang Hengshu H Huang Yuesheng Y Teng Miao M

Scientific reports 20150317

Our previous study suggested that microtubule network alteration affects the process of glycolysis in cardiomyocytes (CMs) via the regulation of hypoxia-inducible factor (HIF)-1α during the early stages of hypoxia. However, little is known regarding the underlying mechanisms of microtubule network alteration-induced changes of HIF-1α. The von Hippel-Lindau tumor suppressor protein (pVHL) has been shown to mediate the ubiquitination of HIF-1α in the nuclear compartment prior to HIF-1α exportation ...[more]

PMID: 25779090

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Project description:Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1 in the adaptive response, however, has not been determined. Here we investigate how HIF-1 influences hypoxic adaptation throughout Drosophila development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in dHIF mutants and that these animals are unable to mobilize glycogen in hypoxia. Furthermore, we find that the estrogen-related receptor (dERR), which is a global regulator of aerobic glycolysis in larvae, is required for a competent hypoxic response. dERR binds to dHIF and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIF in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including upregulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs. Fly eggs were collected onto egg caps with yeast paste . The caps were replaced after overnight incubation periods and kept at 25M-BM-:C, until mid-L2. At mid-L2, larvae were transferred to a fresh egg cap with blue yeast paste (0.3% bromophenol blue), and allowed to develop until achieving the partial clear gut L3 stage (-10 to -4 hrs prior to metamorphic onset). Appropriately staged animals were moved to fresh agar plates and allowed to age an additional 6 hours at 25M-BM-:C (normoxic treatment). Alternatively, animals were placed in an airtight Modular Incubator Chamber for 6 hours at 25M-BM-:C after a gas mixture containing 4% oxygen balanced with nitrogen was flashed into the chamber (hypoxic treatment). Mutant larvae were sorted for the absence of GFP expression using dissecting stereoscope with fluorescence at mid-L2. Microarray analyses were performed on at least three biological replicates of w1118, dHIF mutants, or dERR mutants at the partial clear gut third instar larval stage and were treated for 6 hours in normoxia or 4% O2. For each biological replicate, at least 10 larvae were collected and washed with 1M-CM-^WPBS. Larvae were placed in TRIzol (Invitrogen, Carlsbad, CA) and homogenized using VWR disposable pellet mixer. Total RNA was isolated using a TRIzol/RQ1 DNase (Promega, Madison, WI) hybrid extraction protocol. Template labelings were performed using the GeneChip 3' IVT Express Kit according to the manufacturerM-bM-^@M-^Ys specifications (Affymetrix, Santa Clara, CA). Hybridizations to Affymetrix GeneChip Drosophila Genome 2.0 arrays were performed using the manufacturers recommendations. Every chip was scanned at a high resolution by the Affymetrix GeneChipM-BM-. Scanner 3000 according to the GeneChip Expression Analysis Technical Manual procedures (Affymetrix, Santa Clara, CA).

Dataset Information

Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1? in hypoxic cardiomyocytes.

Publications

Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1α in hypoxic cardiomyocytes.

Similar Datasets

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