ArticleProceedings of the National Academy of Sciences of the United States of America2013
Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
36 citing papers in PubMed, 66 citations in OpenAlex.
- Review
- A Brief Overview of Molecular Biology in Pituitary Adenomas with a Focus on Aggressive Lesions.International journal of molecular sciences · 2025Review
- Genetic models of Cushing's disease : From cells, in vivo transgenic models to human pituitary organoids.Pituitary · 2025Review
- Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.ACS pharmacology & translational science · 2025Article
- Cushing syndrome.Nature reviews. Disease primers · 2025Review
- Review
- Current and Emerging Pharmacological Therapies for Cushing's Disease.Current pharmaceutical design · 2024Review
- Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.Nucleic acids research · 2023Article
- Review
- Gene Mutations in Cushing's Syndrome.Molecular syndromology · 2023Review
- Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing's Syndrome.Endocrine reviews · 2022Review
- The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas.International journal of molecular sciences · 2022Review
- Current and Emerging Medical Therapies in Pituitary Tumors.Journal of clinical medicine · 2022Review
- A human ACTH-secreting corticotroph tumoroid model: Novel Human ACTH-Secreting Tumor Cell in vitro Model.EBioMedicine · 2021Article
- Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT-20 cells.Journal of cellular and molecular medicine · 2021Article
- Recent Understanding and Future Directions of Recurrent Corticotroph Tumors.Frontiers in endocrinology · 2021Review
- Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease.The Journal of clinical endocrinology and metabolism · 2021Article
- Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening.ACS omega · 2020Article
- The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing's Disease.International journal of molecular sciences · 2020Review
- Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription.Cells · 2020Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.