Journal
CELL METABOLISM
Volume 26, Issue 6, Pages 817-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2017.09.001
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Funding
- NIH [R01CA192642, R01CA218254, R01DK108743, R01CA172025, 5P30CA030199, R01CA188652]
- NSF (CAREER) [1454425]
- DOD [W81XWH-13-1-0105]
- CCSPG [5P30CA030199]
- la Caixa'' fellowship
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1454425] Funding Source: National Science Foundation
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Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.
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