ArticleJournal of translational medicine2025
The STUB1-TPIT axis regulates the secretion of adrenocorticotrophic hormone in cushing disease.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundCushing's disease (CD) is a clinical syndrome caused by excessive secretion of adrenocorticotropic hormone (ACTH) from a pituitary corticotroph adenoma, resulting in adrenal cortical hyperplasia and overproduction of cortisol. The T-box transcription factor (TPIT) is crucial for regulating ACTH secretion in pituitary corticotroph adenomas. This study aims to explore the ubiquitin-mediated degradation of TPIT and identify potential pharmaceutical agents for treating CD.
methodsThe TPIT-interacting protein STUB1 was identified via mass spectrometry. The interaction between STUB1 and TPIT was confirmed using NanoBiT and GST pulldown assays. The expression of TPIT, pro-opiomelanocortin (POMC), and STUB1 was assessed by immunoblotting, dual-luciferase reporter assays, quantitative real-time PCR, RNA-sequencing, and immunohistochemistry. ACTH levels were measured by ELISA.
resultsSTIP1 Homology and U-Box Containing Protein 1 (STUB1) interacts with TPIT through its TPR domain and ubiquitinates multiple sites on TPIT via the U-box domain, leading to TPIT degradation. This degradation reduces POMC expression and ACTH secretion in AtT-20 cells. Additionally, STUB1 inhibits cell proliferation both in vitro and in vivo. Clinical investigations revealed that STUB1 expression is significantly lower in ACTH-secreting corticotroph adenomas than in silent corticotroph adenomas (SCAs). A negative correlation was observed between STUB1 and TPIT protein levels, as well as POMC expression. Furthermore, NanoBiT drug screening identified that Irbesartan and Lumiracoxib increased TPIT degradation, thereby reducing POMC expression and ACTH secretion.
conclusionSTUB1 is a promising therapeutic target for CD and drugs targeting the STUB1-TPIT complex may provide a potential treatment approach.
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