Journal article
Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma
Molecular cancer research, Vol.9(9), pp.1255-1265
09/2011
DOI: 10.1158/1541-7786.MCR-11-0302
PMCID: PMC3234675
PMID: 21798997
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.
Details
- Title: Subtitle
- Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma
- Creators
- Blanka Kucejova - Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USASamuel Peña-LlopisToshinari YamasakiSharanya SivanandTram Anh T TranShane AlexanderNicholas C WolffYair LotanXian-Jin XieWareef KabbaniPayal KapurJames Brugarolas
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.9(9), pp.1255-1265
- Publisher
- United States
- DOI
- 10.1158/1541-7786.MCR-11-0302
- PMID
- 21798997
- PMCID
- PMC3234675
- ISSN
- 1557-3125
- eISSN
- 1557-3125
- Grant note
- K08 NS051843 / NINDS NIH HHS R01 CA129387 / NCI NIH HHS R01CA129387 / NCI NIH HHS R44 CA126087 / NCI NIH HHS T32CA124334 / NCI NIH HHS R43 CA126087 / NCI NIH HHS K08 NS051843-05 / NINDS NIH HHS F32CA126087 / NCI NIH HHS T32 CA124334 / NCI NIH HHS R01 CA129387-05 / NCI NIH HHS K08NS051843 / NINDS NIH HHS
- Language
- English
- Date published
- 09/2011
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917773302771
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