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SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways.
Oncogene
November 2024
Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
High-grade serous ovarian cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to ferroptosis in HGSOC.
View Article and Find Full Text PDFLocalization and function of humanized F508del-CFTR in mouse intestine following activation of serum glucocorticoid kinase 1 and Trikafta.
Eur J Pharmacol
September 2024
Department of Pediatrics/Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT, USA; Department of Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. Electronic address:
The CFTR modulator Trikafta has markedly improved lung disease for Cystic Fibrosis (CF) patients carrying the common delta F508 (F508del-CFTR) CFTR mutation. F508del-CFTR results in an apical trafficking defect and loss of function in CFTR-expressing epithelial cells. However, Trikafta has not resulted in improved gastrointestinal function in CF patients.
View Article and Find Full Text PDFPatient-derived enteroids provide a platform for the development of therapeutic approaches in microvillus inclusion disease.
J Clin Invest
October 2023
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes.
View Article and Find Full Text PDFInteractions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt.
J Biol Chem
September 2022
Department of Medicine, Division of Nephrology, and Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA. Electronic address:
Mechanistic target of rapamycin complex 2 (mTORC2) is a multi-subunit kinase complex, central to multiple essential signaling pathways. Two core subunits, Rictor and mSin1, distinguish it from the related mTORC1 and support context-dependent phosphorylation of its substrates. mTORC2 structures have been determined previously; however, important questions remain, particularly regarding the structural determinants mediating substrate specificity and context-dependent activity.
View Article and Find Full Text PDFLoss of Serum Glucocorticoid-Inducible Kinase 1 SGK1 Worsens Malabsorption and Diarrhea in Microvillus Inclusion Disease (MVID).
J Clin Med
July 2022
Department of Pediatrics, Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06510, USA.
Article Synopsis
- Microvillus inclusion disease (MVID) is a severe congenital diarrhea condition linked to mutations in the MYO5B gene, impacting fluid secretion and nutrient absorption in the intestines.
- Researchers tested the role of serum glucocorticoid-inducible kinase 1 (SGK1) in MVID using genetically modified mice, discovering that loss of SGK1 worsened symptoms by exacerbating carbohydrate malabsorption.
- The study found that while MYO5B was impairing fluid secretion and leading to diarrhea, the absence of SGK1 led to even more severe diarrhea despite some preservation of the CFTR protein essential for intestinal fluid regulation.
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