ArticleMolecular cancer research : MCR2011
Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma.
Article in Molecular cancer research : MCR, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 2 of them syntheses that pooled it.
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Who cites it
72 citing papers in PubMed, 2 syntheses or guidelines pooled it, 109 citations in OpenAlex.
- Eosinophilic Solid and Cystic Renal Cell Carcinoma-A Systematic Review and Meta-Analysis.International journal of molecular sciences · 2024Pooled it
- Metabolism of kidney cancer: from the lab to clinical practice.European urology · 2013Pooled it
- PCDHGC3 silencing promotes clear cell renal cell carcinoma metastasis via mTOR/HIF2α activation, lipid metabolism rewiring, and ferroptosis evasion.Cell death & disease · 2026Article
- The mechanism of the PI3K-AKT-mTOR signaling pathway in renal cell carcinoma: current developments and future prospects.Frontiers in oncology · 2026Review
- Lower cytoplasmic expression of DDIT4 is associated with poor prognosis in gastric cancer patients.Discover oncology · 2025Article
- Increased nuclear expression of DNA damage inducible transcript 4 can serve as a potential prognostic biomarker in patients with gliomas: a study based on data mining and experimental tools.Discover oncology · 2025Article
- Extensive genotype-phenotype heterogeneity in renal cell carcinoma - a proof-of-concept study.Frontiers in oncology · 2025Article
- Genetics, Pathophysiology, and Current Challenges in Von Hippel-Lindau Disease Therapeutics.Diagnostics (Basel, Switzerland) · 2024Review
- Unconventional mechanism of action and resistance to rapalogs in renal cancer.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Nuclear overexpression of DNA damage-inducible transcript 4 (DDIT4) is associated with aggressive tumor behavior in patients with pancreatic tumors.Scientific reports · 2023Article
- Review
- Differential Activation of NRF2 Signaling Pathway in Renal-Cell Carcinoma Caki Cell Lines.Biomedicines · 2023Article
- Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2022Article
- Autophagy regulated by the HIF/REDD1/mTORC1 signaling is progressively increased during erythroid differentiation under hypoxia.Frontiers in cell and developmental biology · 2022Article
- Review
- Afatinib induces pro-survival autophagy and increases sensitivity to apoptosis in stem-like HNSCC cells.Cell death & disease · 2021Article
- VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma.Scientific reports · 2021Article
- Von Hippel-Lindau tumor suppressor pathways & corresponding therapeutics in kidney cancer.Journal of genetics and genomics = Yi chuan xue bao · 2021Review
- High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer.Scientific reports · 2021Article
- Article
12 more citing papers are in PubMed but not listed here.
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12 authors at 1 institution in 1 country.
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Abstract
mTOR complex 1 (mTORC1) is implicated in cell growth control and is extensively regulated. We previously reported that in response to hypoxia, mTORC1 is inhibited by the protein regulated in development and DNA damage response 1 (REDD1). REDD1 is upregulated by hypoxia-inducible factor (HIF)-1, and forced REDD1 expression is sufficient to inhibit mTORC1. REDD1-induced mTORC1 inhibition is dependent on a protein complex formed by the tuberous sclerosis complex (TSC)1 and 2 (TSC2) proteins. In clear-cell renal cell carcinoma (ccRCC), the von Hippel-Lindau (VHL) gene is frequently inactivated leading to constitutive activation of HIF-2 and/or HIF-1, which may be expected to upregulate REDD1 and inhibit mTORC1. However, mTORC1 is frequently activated in ccRCC, and mTORC1 inhibitors are effective against this tumor type; a paradox herein examined. REDD1 was upregulated in VHL-deficient ccRCC by in silico microarray analyses, as well as by quantitative real-time PCR, Western blot, and immunohistochemistry. Vhl disruption in a mouse model was sufficient to induce Redd1. Using ccRCC-derived cell lines, we show that REDD1 upregulation in tumors is VHL dependent and that both HIF-1 and HIF-2 are, in a cell-type-dependent manner, recruited to, and essential for, REDD1 induction. Interestingly, whereas mTORC1 is responsive to REDD1 in some tumors, strategies have evolved in others, such as mutations disrupting TSC1, to subvert mTORC1 inhibition by REDD1. Sequencing analyses of 77 ccRCCs for mutations in TSC1, TSC2, and REDD1, using PTEN as a reference, implicate the TSC1 gene, and possibly REDD1, as tumor suppressors in sporadic ccRCC. Understanding how ccRCCs become refractory to REDD1-induced mTORC1 inhibition should shed light into the development of ccRCC and may aid in patient selection for molecular-targeted therapies.
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