Hypoxia-Inducible Factor/MAZ-Dependent Induction of Caveolin-1 Regulates Colon Permeability through Suppression of Occludin, Leading to Hypoxia-Induced Inflammation

Xie, Liwei; Xue, Xiang; Taylor, Matthew J.; Ramakrishnan, S; Nagaoka, Kenjiro; Hao, Cathy; Gonzalez, Frank J.; Shah, Yatrik M.

doi:10.1128/mcb.00324-14

Cited by 60 publications

(65 citation statements)

References 55 publications

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“…Indeed, IR increased ROS in the intestine followed by the direct recruitment of HIF-1α to the Wnt2b promoter and subsequent Wnt2b transactivation (see Figures 4J, 4P). Furthermore, given the inhibitory effects of Chet on both HIF-1α and HIF-2α and the protective role of HIF-2α in the intestine (Taniguchi, et al, 2014; Xie, et al, 2014), HIF-2α might also be involved in ROS-mediated Wnt2b transactivation.…”

Section: Discussionmentioning

confidence: 99%

Quiescence Exit of Tert+ Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration

et al. 2017

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SUMMARY Fine control of stem cell maintenance and activation is crucial for tissue homeostasis and regeneration. However, the mechanism of quiescence exit of Tert+ intestinal stem cells (ISCs) remains unknown. Employing a Tert knock-in (TertTCE/+) mouse model, we found that Tert+ cells are long-term label-retaining self-renewing cells, which are partially distinguished from the previously identified +4 intestinal stem cells (ISCs). Tert+ cells become mitotic upon irradiation (IR) injury. Conditional ablation of Tert+ cells impairs IR-induced intestinal regeneration but not intestinal homeostasis. Upon IR injury, Wnt signaling is specifically activated in Tert+ cells via the ROS-HIFs-transactivated Wnt2b signaling axis. Importantly, conditional knock-out of β-catenin/Ctnnb1 in Tert+ cells undermines IR-induced quiescence exit of Tert+ cells, which subsequently impedes intestinal regeneration. Our results strongly suggest that Wnt signaling-induced activation of Tert+ ISCs is indispensable for intestinal regeneration, which unveils the underlying mechanism of how Tert+ stem cells undergo quiescence exit upon tissue injury.

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Section: Discussionmentioning

confidence: 99%

Quiescence Exit of Tert+ Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration

et al. 2017

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“…These beneficial roles are likely mediated through inhibiting SOCE and the expression of SOCCs channel protein TRPCs, which then lead to suppressed proliferation and migration of PASMCs (11,13). Previous studies have reported that, in cancer cell lines, caveolin-1 acts as a direct transcription target of the main hypoxic regulator, hypoxia-inducible factors 1 and 2, and facilitates the proproliferative consequences during the process of tumorigenesis (47,48). Interestingly, the effects of PPARg on caveolin-1 vary considerably in different cell types.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptor γ–Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1–Dependent Mechanism

Yang

Qian

et al. 2015

Am J Respir Cell Mol Biol

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Our previous publication demonstrated that peroxisome proliferator-activated receptor g (PPARg) inhibits the pathogenesis of chronic hypoxia (CH)-induced pulmonary hypertension by targeting store-operated calcium entry (SOCE) in rat distal pulmonary arterial smooth muscle cells (PASMCs). In this study, we aim to determine the role of a membrane scaffolding protein, caveolin-1, during the suppressive process of PPARg on SOCE. Adult (6-8 weeks) male Wistar rats (200-250 g) were exposed to CH (10% O 2 ) for 21 days to establish CH-induced pulmonary hypertension. Primary cultured rat distal PASMCs were applied for the molecular biological experiments. First, hypoxic exposure led to 2.5-fold and 1-fold increases of caveolin-1 protein expression in the distal pulmonary arteries and PASMCs, respectively. Second, effective knockdown of caveolin-1 significantly reduced hypoxia-induced SOCE for 58.2% and 41.5%, measured by Mn 21 quenching and extracellular Ca 21 restoration experiments, respectively. These results suggested that caveolin-1 acts as a crucial regulator of SOCE, and hypoxia-up-regulated caveolin-1 largely accounts for hypoxia-elevated SOCE in PASMCs. Then, by using a high-potency PPARg agonist, GW1929, we detected that PPARg activation inhibited SOCE and caveolin-1 protein for 62.5% and 59.8% under hypoxia, respectively, suggesting that caveolin-1 also acts as a key target during the suppressive process of PPARg on SOCE in PASMCs. Moreover, by using effective small interfering RNAs against PPARg and caveolin-1, and PPARg antagonist, T0070907, we observed that PPARg plays an inhibitory role on caveolin-1 protein by promoting its lysosomal degradation, without affecting the messenger RNA level. PPARg inhibits SOCE, at least partially, by suppressing cellular caveolin-1 protein in PASMCs.Keywords: pulmonary hypertension; peroxisome proliferator-activated receptor g; caveolin-1; store-operated calcium entry; pulmonary arterial smooth muscle cells Pulmonary hypertension (PH) is a severe pulmonary vascular disease characterized by sustained increase in the pulmonary arterial pressure and excessive thickening and remodeling of the distal small pulmonary arteries (PAs). These functional and structural changes then lead to right ventricular hypertrophy and, eventually, heart failure. Nowadays, it is well accepted that the dysregulation of the proliferation and migration of the PA smooth muscle cells (PASMCs) are the main reasons contributing to the abnormally excessive thickening and remodeling of the distal PAs during PH pathogenesis (1-3).Previous studies have described that the increase of the intracellular free calcium concentration ([Ca 21 ] i ) acts a major factor

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“…Colon permeability was assessed with FITC-labeled dextran (FD4; Sigma-Aldrich) as previously described (41). Quantitative Real-Time RT-PCR.…”

Section: Methodsmentioning

confidence: 99%

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

Xue

Bredell

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory bowel disease (IBD) is a chronic inflammatory disorder and is a major risk factor for colorectal cancer (CRC). Hypoxia is a feature of IBD and modulates cellular and mitochondrial metabolism. However, the role of hypoxic metabolism in IBD is unclear. Because mitochondrial dysfunction is an early hallmark of hypoxia and inflammation, an unbiased proteomics approach was used to assess the mitochondria in a mouse model of colitis. Through this analysis, we identified a ferrireductase: six-transmembrane epithelial antigen of prostate 4 (STEAP4) was highly induced in mouse models of colitis and in IBD patients. STEAP4 was regulated in a hypoxia-dependent manner that led to a dysregulation in mitochondrial iron balance, enhanced reactive oxygen species production, and increased susceptibility to mouse models of colitis. Mitochondrial iron chelation therapy improved colitis and demonstrated an essential role of mitochondrial iron dysregulation in the pathogenesis of IBD. To address if mitochondrial iron dysregulation is a key mechanism by which inflammation impacts colon tumorigenesis, STEAP4 expression, function, and mitochondrial iron chelation were assessed in a colitis-associated colon cancer model (CAC). STEAP4 was increased in human CRC and predicted poor prognosis. STEAP4 and mitochondrial iron increased tumor number and burden in a CAC model. These studies demonstrate the importance of mitochondrial iron homeostasis in IBD and CRC.

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Hypoxia-Inducible Factor/MAZ-Dependent Induction of Caveolin-1 Regulates Colon Permeability through Suppression of Occludin, Leading to Hypoxia-Induced Inflammation

Cited by 60 publications

References 55 publications

Quiescence Exit of Tert+ Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration

Quiescence Exit of Tert+ Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration

Peroxisome Proliferator–Activated Receptor γ–Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1–Dependent Mechanism

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

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