Central Role of the Oxygen-dependent Degradation Domain of<i>Drosophila</i>HIFα/Sima in Oxygen-dependent Nuclear Export

Irisarri, Maximiliano; Lavista-Llanos, Sofía; Romero, Nuria; Centanin, Lázaro; Dekanty, Andrés; Wappner, Pablo

doi:10.1091/mbc.e09-01-0038

Cited by 16 publications

(19 citation statements)

References 45 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4, 5, and 6); the disparity in p-ERK levels among cell lines is likely related to their VHL status, as HIF-1α (which is destabilized by wild-type VHL) lies upstream of ERK. 25 Additional differences were apparent decreased CRM1 and increased nuclear p53 levels by KPT-185 (Fig 1, 4, and 5): sorafenib did not change these protein levels in all three cell lines (Supplemental Data Fig. 4).…”

Section: Resultsmentioning

confidence: 88%

See 1 more Smart Citation

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

et al. 2013

View full text Add to dashboard Cite

Since renal cell carcinoma (RCC) often presents asymptomatically, patients are commonly diagnosed at the metastatic stage when treatment options are limited and survival is poor. Given that progression-free survival with current therapies for metastatic RCC is only one to two years and existing drugs are associated with a high rate of resistance, new pharmacological targets are desperately needed. We identified and evaluated the nuclear exporter protein, chromosome region maintenance protein 1 (CRM1), as a novel potential therapeutic for RCC. Purpose To evaluate novel, selective inhibitors of nuclear export as potential RCC therapeutics. Materials and Methods Efficacy of the CRM1 inhibitors, KPT-185 and -251, was tested in several RCC cell lines and in a RCC xenograft model. Apoptosis and cell cycle arrest were quantified, and localization of p53 family proteins was assessed using standard techniques. Results KPT-185 attenuated CRM1 and showed increased cytotoxicity in RCC cells in vitro, with evidence of increased apoptosis as well as cell cycle arrest. KPT-185 caused both p53 and p21 to remain primarily in the nucleus in all RCC cell lines, suggesting a mechanism of action of these compounds dependent upon tumor-suppressor protein localization. Furthermore, when administered orally in a high-grade RCC xenograft model, the bioavailable CRM1 inhibitor KPT-251 significantly inhibited tumor growth in vivo with the expected on-target effects and with no obvious toxicity. Conclusions The CRM1 inhibitor family of proteins are novel therapeutic targets RCC and deserve further intensive investigation in this and other urologic malignancies.

show abstract

Section: Resultsmentioning

confidence: 88%

“…It is possible that p-ERK level in VHL negative cells is more sensitive to CRM1 inhibition than in VHL wild type cells since CRM1 is one of the major regulators when VHL is absent. 25 …”

Section: Discussionmentioning

confidence: 99%

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

et al. 2013

View full text Add to dashboard Cite

show abstract

“…To avoid confusion, in the present study, we use "normoxia" for the atmospheric oxygen concentration of 21%, traditionally used in tissue culture, and "hypoxia" for conditions of reduced oxygen tensions. Although these terms are used for athletes training on the mountain 2) , this nomenclature has also been used for culture conditions in the literature as well [9][10][11][12] . Against this background, many investigations have been performed to elucidate the effects of hypoxia on proliferation and differentiation of myoblasts 1 3 ) .…”

Section: Introductionmentioning

confidence: 99%

Differential Responses of Myogenic C2C12 Cells to Hypoxia between Growth and Muscle-Induction Phases: Growth, Differentiation and Motility

et al. 2011

View full text Add to dashboard Cite

Abstract.[Introduction] Local hypoxia plays a favorable role in muscle regeneration. [Subjects and Methods] The effect of hypoxia on cell growth, differentiation, and motility was examined in differentiating and growing C2C12 mouse myoblasts cells, respectively.[Results] Hypoxia induced growth suppression in the growth phase, but the suppression diminished in the differentiation phase. Hypoxia inhibited the expression of differentiation marker proteins, accompanying MyoD mRNA suppression. Expression of HIF-1α protein was induced only in the induction phase, regardless of oxygen concentration. Hypoxia did not alter motile activity in the growing phase, but augmented the motile property in the differentiation phase. Expression of autocrine motility factor mRNA was augmented under hypoxic conditions. [Conclusion] In differentiating cells, HIF-1α induced by myogenic differentiation may compensate for the cell growth suppression due to hypoxia, and support the motility augmentation. Hypoxia may shift differentiating cells into the growth phase which provides the ability to translocate to an appropriate area.

show abstract

“…Hif-1α is a key regulator of tissue responses to changes in oxygen tension. The Drosophila homolog of Hif-1α, Similar (Sima), like its mammalian counterpart is hydroxylated and degraded by the proteasome under normoxia (Irisarri et al, 2009;Romero et al, 2008). When tissues become hypoxic, Sima drives the transcription of hypoxia-related genes (Lisy and Peet, 2008).…”

Section: Reciprocal Interactions Between Hypoxia-related Signaling Pamentioning

confidence: 99%

TrpML-mediated astrocyte microdomain Ca²⁺ transients regulate astrocyte-tracheal interactions

Freeman

2019

Preprint

View full text Add to dashboard Cite

Astrocytes exhibit spatially-restricted near membrane microdomain Ca 2+ transients in their fine processes. How these transients are generated, and how they regulate brain function in vivo remain unclear. Here we show that Drosophila astrocytes exhibit spontaneous, activity-independent microdomain Ca 2+ transients in their fine processes.Astrocyte microdomain Ca 2+ transients are mediated by the TRP channel TrpML, stimulated by reactive oxygen species (ROS), and can be enhanced in frequency by tyramine via the TyrRII receptor. Interestingly, astrocyte microdomain Ca 2+ transients are closely associated with tracheal elements, which dynamically extend filopodia throughout the nervous system, and astrocyte microdomain Ca 2+ transients precede retraction of tracheal filopodia. Loss of TrpML leads to increased tracheal filopodial numbers and growth, and increased ROS in the CNS. Basal levels of astrocyte microdomain Ca 2+ transient signaling were regulated by the hypoxia-sensitive factor Sima/Hif-1, providing a link between astrocyte-tracheal interactions and the molecular control of CNS gas exchange. We propose that local ROS production regulates tracheal dynamics through TrpML-dependent modulation of astrocyte microdomain Ca 2+ transients, and in turn CNS gas exchange.

show abstract

Central Role of the Oxygen-dependent Degradation Domain ofDrosophilaHIFα/Sima in Oxygen-dependent Nuclear Export

Cited by 16 publications

References 45 publications

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

Differential Responses of Myogenic C2C12 Cells to Hypoxia between Growth and Muscle-Induction Phases: Growth, Differentiation and Motility

TrpML-mediated astrocyte microdomain Ca²⁺ transients regulate astrocyte-tracheal interactions

Contact Info

Product

Resources

About

Central Role of the Oxygen-dependent Degradation Domain ofDrosophilaHIFα/Sima in Oxygen-dependent Nuclear Export

Cited by 16 publications

References 45 publications

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth

Differential Responses of Myogenic C2C12 Cells to Hypoxia between Growth and Muscle-Induction Phases: Growth, Differentiation and Motility

TrpML-mediated astrocyte microdomain Ca2+ transients regulate astrocyte-tracheal interactions

Contact Info

Product

Resources

About

TrpML-mediated astrocyte microdomain Ca²⁺ transients regulate astrocyte-tracheal interactions