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Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2011 Sep; Vol. 9 (9), pp. 1255-65. Date of Electronic Publication: 2011 Jul 28. - Publication Year :
- 2011
-
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.<br /> (©2011 AACR.)
- Subjects :
- Animals
Basic Helix-Loop-Helix Transcription Factors genetics
Basic Helix-Loop-Helix Transcription Factors metabolism
Gene Expression Regulation, Neoplastic
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Mice
RNA, Small Interfering genetics
Sequence Analysis
Signal Transduction
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Cells, Cultured
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Carcinoma, Renal Cell genetics
Carcinoma, Renal Cell metabolism
Transcription Factors genetics
Transcription Factors metabolism
Von Hippel-Lindau Tumor Suppressor Protein genetics
Von Hippel-Lindau Tumor Suppressor Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 9
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 21798997
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-11-0302