Loss of Phosphatase and Tensin Homolog (PTEN) Induces Leptin-mediated Leptin Gene Expression

Pathak, Rashmi; Grover, Aditya; Malaney, Prerna; Quarni, Waise; Pandit, Ashish; Allen‐Gipson, Diane; Davé, Vrushank

doi:10.1074/jbc.m113.481523

Cited by 17 publications

(13 citation statements)

References 86 publications

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“…Using an independently-generated genetic dataset (Pathak et al, 2013), we corroborated these in-vitro findings in-vivo and in non-malignant tissue. Increased PDHK1 levels were present in normal murine lung epithelium in which PTEN was genetically-inactivated in-vivo compared to lung epithelium from PTEN WT control mice ( Figure S2C), suggesting physiological regulation of PDHK1 expression by PTEN in-vivo.…”

Section: Pten Deficiency Upregulates Pdhk1 Expression In Normal and Csupporting

confidence: 57%

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

Chatterjee

Pazarentzos

Hrustanovic

et al. 2018

Preprint

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PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells.The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NFkB activating protein (NKAP) and limits NFkB activation to suppress expression of PDHK1, a NFkB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTENdeficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.

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Section: Pten Deficiency Upregulates Pdhk1 Expression In Normal and Csupporting

confidence: 57%

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

Chatterjee

Pazarentzos

Hrustanovic

et al. 2018

Preprint

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“…4c). Many STAT3 downstream molecules (FST, LYZ, HP, SNAI2 and LEPR) 11–16 were also present at significantly higher levels in pneumotype SPT than in pneumotype BPT (Supplementary Fig. 8).…”

Section: Resultsmentioning

confidence: 99%

Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype

et al. 2016

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Microaspiration is a common phenomenon in healthy subjects, but its frequency is increased in chronic inflammatory airway diseases, and its role in inflammatory and immune phenotypes is unclear. We have previously demonstrated that acellular bronchoalveolar lavage samples from half of the healthy people examined are enriched with oral taxa (here called pneumotypeSPT) and this finding is associated with increased numbers of lymphocytes and neutrophils in bronchoalveolar lavage. Here, we have characterized the inflammatory phenotype using a multi-omic approach. By evaluating both upper airway and acellular bronchoalveolar lavage samples from 49 subjects from three cohorts without known pulmonary disease, we observed that pneumotypeSPT was associated with a distinct metabolic profile, enhanced expression of inflammatory cytokines, a pro-inflammatory phenotype characterized by elevated Th-17 lymphocytes and, conversely, a blunted alveolar macrophage TLR4 response. The cellular immune responses observed in the lower airways of humans with pneumotypeSPT indicate a role for the aspiration-derived microbiota in regulating the basal inflammatory status at the pulmonary mucosal surface.

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“…16527) 56 and β -catenin reporter (TOP-FLASH) 57 were transfected using the polyethylenimine method 58 with modifications as described previously. 59 Wnt reporter fibroblast 3T3 mouse fibroblast cell line was used to assess Wnt- and TGF- β -mediated β -catenin transcriptional activity with and without FAK-inhibitor. PF-573 228 was used as a FAK inhibitor in the transcriptional studies (Selleckchem, Houston, TX, USA; no.…”

Section: Methodsmentioning

confidence: 99%

“…59 Five hundred nanograms of purified RNA was converted into cDNA using the qScript cDNA SuperMix (Quanta Biosciences, Beverly, MA, USA; no. 95048-100) and used for real-time polymerase chain reaction (RT-PCR) assays.…”

Section: Methodsmentioning

confidence: 99%

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Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

et al. 2017

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Idiopathic pulmonary fibrosis (IPF) is characterized by lung remodeling arising from epithelial injury, aberrant fibroblast growth, and excessive deposition of extracellular matrix. Repeated epithelial injury elicits abnormal wound repair and lung remodeling, often associated with alveolar collapse and edema, leading to focal hypoxia. Here, we demonstrate that hypoxia is a physiological insult that contributes to pulmonary fibrosis (PF) and define its molecular roles in profibrotic activation of lung epithelial cells. Hypoxia increased transcription of profibrotic genes and altered the proteomic signatures of lung epithelial cells. Network analysis of the hypoxic epithelial proteome revealed a crosstalk between transforming growth factor-β1 and FAK1 (focal adhesion kinase-1) signaling, which regulated transcription of galectin-1, a profibrotic molecule. Galectin-1 physically interacted with and activated FAK1 in lung epithelial cells. We developed a novel model of exacerbated PF wherein hypoxia, as a secondary insult, caused PF in mice injured with subclinical levels of bleomycin. Hypoxia elevated expression of phosphorylated FAK1, galectin-1, and α-smooth muscle actin and reduced caspase-3 activation, suggesting aberrant injury repair. Galectin-1 inhibition caused apoptosis in the lung parenchyma and reduced FAK1 activation, preventing the development of hypoxia-induced PF. Galectin-1 inhibition also attenuated fibrosis-associated lung function decline. Further, galectin-1 transcript levels were increased in the lungs of IPF patients. In summary, we have identified a profibrotic role of galectin-1 in hypoxia signaling driving PF.

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Loss of Phosphatase and Tensin Homolog (PTEN) Induces Leptin-mediated Leptin Gene Expression

Cited by 17 publications

References 86 publications

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

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