Development of Cytosolic Hypoxia and Hypoxia-inducible Factor Stabilization Are Facilitated by Aquaporin-1 Expression

Laboratorio de Investigaciones Biomédicas, Departamento de Fisiología Médica y Biofísica, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, 41013 Spain.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2007; 282(41):30207-15. DOI: 10.1074/jbc.M702639200
Source: PubMed


O(2) is essential for aerobic life, and the classic view is that it diffuses freely across the plasma membrane. However, measurements of O(2) permeability of lipid bilayers have indicated that it is much lower than previously thought, and therefore, the existence of membrane O(2) channels has been suggested. We hypothesized that, besides its role as a water channel, aquaporin-1 (AQP-1) could also work as an O(2) transporter, because this transmembrane protein appears to be CO(2)-permeable and is highly expressed in cells with rapid O(2) turnover (erythrocytes and microvessel endothelium). Here we show that in mammalian cells overexpressing AQP-1 and exposed to hypoxia, the loss of cytosolic O(2), as well as stabilization of the O(2)-dependent hypoxia-inducible transcription factor and expression of its target genes, is accelerated. In normoxic endothelial cells, knocking down AQP-1 produces induction of hypoxia-inducible genes. Moreover, lung AQP-1 is markedly up-regulated in animals exposed to hypoxia. These data suggest that AQP-1 has O(2) permeability and thus could facilitate O(2) diffusion across the cell membrane.

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Available from: Miriam Echevarría, Oct 19, 2015
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    • "AZA decreased the expression of AQP5, cell proliferation and migration[21]Colon cancer Acetazolamide decreased AQP1 expression and the tumor growth.[6]AQP1 induced HT20 cell migration[50]AQP1 is required for angiogenesis[3]hEGF induced AQP3 expression, proliferation and migration. AQP3 is correlated lymph node differentiation and metastasis in CRC. "
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    ABSTRACT: Aquaporins (AQPs) are small (~30kDa monomers) integral membrane water transport proteins that allow water to flow through cell membranes in reaction to osmotic gradients in cells. In mammals, the family of AQPs has thirteen (AQP0-12) unique members that mediate critical biological functions. Since AQPs can impact cell proliferation, migration and angiogenesis, their role in various human cancers is well established. Recently, AQPs have been explored as potential diagnostic and therapeutic targets in gastrointestinal (GI) cancers. GI cancers encompass multiple sites including the colon, esophagus, stomach and pancreas. Research in the last three decades has revealed biological aspects and signaling pathways critical for the development of GI cancers. Since the majority of these cancers is very aggressive and rapidly metastasizes, identifying effective targets is crucial for treatment. Preclinical studies have utilized inhibitors of specific AQPs and knock down of AQP expression using siRNA. Although several studies have explored the role of AQPs in colorectal, esophageal, gastric, hepatocellular and pancreatic cancers, there is no comprehensive review compiling the available information on GI cancers as has been published for other malignancies such as ovarian cancer. Due to the similarities and association of various sites of GI cancers, it is helpful to consider these results collectively in order to better understand the role of specific AQPs in critical GI cancers. This review summarizes the current knowledge of the role of AQPs in GI malignancies with particular focus on diagnosis and therapeutic applications.
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    • "The resuspended pellet was left on ice 5 min, vortex, and then centrifuged at 16,000g for 15 min at 4°C, and extracted proteins remain in the supernatant. Protein concentration was analyzed with the Bradford method (BioRad Protein Assay, BioRad, Berkeley, CA) and kept at –20°C until Western blot assay (Echevarría et al., 2007). Afterwards, 20–40 mg of whole-cell extracts were resolved by SDS–PAGE (10%) for AQP3 and Cyclin A, B1, D1, and E. After electrophoresis, proteins were transferred into PVDF membranes (Hybond-P, Amersham Biosciences, Pittsburgh, PA) using a Novex apparatus (Novel Experimental Technology, San Diego, CA). "
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    • "This study demonstrated that pulmonary edema associated with oral gavage in the acute toxicity test was categorized as alveologenic edema exhibiting higher AQP-1 and -4 expression (Fig. 1M-W) than in the sub-chronic test (Table 2). Lung AQP-1 is markedly upregulated in animals exposed to hypoxia, suggesting that AQP-1 has O2 permeability and thus could facilitate O2 diffusion across the cell membrane37. AQP-4 mRNA expression is upregulated on the alveolar type II cell membrane to regulate the exchange of fluid between the alveolar space and alveolar epithelium barrier and play an important compensational role in pulmonary liquid clearance in the event of sodium transport damages in acute lung injury19,45. "
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