ArticleProceedings of the National Academy of Sciences of the United States of America2009
Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 142 papers, 1 of them a synthesis that pooled it.
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Who cites it
142 citing papers in PubMed, 1 synthesis or guideline pooled it, 227 citations in OpenAlex.
- Metabolism of kidney cancer: from the lab to clinical practice.European urology · 2013Pooled it
- Trial
- mTORC1 activation induces B7-H3-dependent metabolic reprogramming in renal cell carcinoma (RCC).Oncogene · 2026Article
- Parathyroid Carcinoma: From Molecular Pathogenesis and Diagnostic Biomarkers to Targeted Therapeutics.International journal of molecular sciences · 2026Review
- Hyperactivation of mTORC1 signaling mediates folliculin deficiency-induced pulmonary cyst formation in Birt-Hogg-Dubé syndrome.The Journal of clinical investigation · 2026Article
- Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome.Frontiers in oncology · 2026Review
- Adjuvant therapy in chromophobe renal cell carcinoma: current evidence and unmet needs.Frontiers in oncology · 2026Review
- FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.Autophagy reports · 2026Article
- High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations.BMC biology · 2025Article
- Folliculin Deletion in the Mouse Kidney Results in Cystogenesis of the Loops of Henle via Aberrant TFEB Activation.The American journal of pathology · 2025Article
- Thyroid Carcinoma in Birt-Hogg-Dubé Syndrome: Case Series and Review of Literature.Thyroid : official journal of the American Thyroid Association · 2025Review
- Differential Diagnosis and a Novel Mutation in Birt-Hogg-Dubé Syndrome: Insights from 2 Cases.The American journal of case reports · 2025Article
- FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency.Current issues in molecular biology · 2025Review
- Heritable hyperparathyroidism: Genetic insights and clinical implications.Best practice & research. Clinical endocrinology & metabolism · 2025Review
- A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress.Scientific reports · 2025Article
- A Comparative Genomic Analysis of Parathyroid Adenomas and Carcinomas Harboring Heterozygous Germline CDC73 Mutations.The Journal of clinical endocrinology and metabolism · 2025Article
- mTORC1, the maestro of cell metabolism and growth.Genes & development · 2025Review
- Clinical and genetic investigations of five Chinese families with Birt-Hogg-Dubé syndrome: a long-term follow-up study.Frontiers in medicine · 2025Article
- Review
- Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research.Cell death & disease · 2024Review
82 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Germline mutations in the BHD/FLCN tumor suppressor gene predispose patients to develop renal tumors in the hamartoma syndrome, Birt-Hogg-Dubé (BHD). BHD encodes folliculin, a protein with unknown function that may interact with the energy- and nutrient-sensing AMPK-mTOR signaling pathways. To clarify BHD function in the mouse, we generated a BHD knockout mouse model. BHD homozygous null (BHD(d/d)) mice displayed early embryonic lethality at E5.5-E6.5, showing defects in the visceral endoderm. BHD heterozygous knockout (BHDd(/+)) mice appeared normal at birth but developed kidney cysts and solid tumors as they aged (median kidney-lesion-free survival = 23 months, median tumor-free survival = 25 months). As observed in human BHD kidney tumors, three different histologic types of kidney tumors developed in BHD(d/+) mice including oncocytic hybrid, oncocytoma, and clear cell with concomitant loss of heterozygosity (LOH), supporting a tumor suppressor function for BHD in the mouse. The PI3K-AKT pathway was activated in both human BHD renal tumors and kidney tumors in BHD(d/+) mice. Interestingly, total AKT protein was elevated in kidney tumors compared to normal kidney tissue, but without increased levels of AKT mRNA, suggesting that AKT may be regulated by folliculin through post translational or post-transcriptional modification. Finally, BHD inactivation led to both mTORC1 and mTORC2 activation in kidney tumors from BHD(d/+) mice and human BHD patients. These data support a role for PI3K-AKT pathway activation in kidney tumor formation caused by loss of BHD and suggest that inhibitors of both mTORC1 and mTORC2 may be effective as potential therapeutic agents for BHD-associated kidney cancer.
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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.