{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:05:55Z","timestamp":1792001155342,"version":"4.4.0"},"reference-count":61,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Research has shown extensive metabolic remodeling in clear cell renal cell carcinoma (ccRCC), with increased glutathione (GSH) levels. We hypothesized that activating transcription factor\u20104 (ATF4) and the integrated stress response (ISR) induce a metabolic shift, including increased GSH accumulation, and that Vitamin A deficiency (VAD), found in ccRCCs, can also activate ATF4 signaling in the kidney. To determine the role of ATF4, we used publicly available RNA sequencing (RNA\u2010seq) data sets from The Cancer Genomics Atlas. Subsequently, we performed RNA\u2010seq and liquid chromatography\u2013mass spectrometry\u2010based metabolomics analysis of the murine TRAnsgenic Cancer of the Kidney (TRACK) model for early\u2010stage ccRCC. To validate our findings, we generated RCC4 cell lines with ATF4 gene edits (ATF4\u2010knockout [KO]) and subjected these cells to metabolic isotope tracing. Analysis of variance, the two\u2010sided Student's <jats:italic>t<\/jats:italic> test, and gene set enrichment analysis were used (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) to determine statistical significance. Here we show that most human ccRCC tumors exhibit activation of the transcription factor ATF4. Activation of ATF4 is concomitant with enrichment of the ATF4 gene set and elevated expression of ATF4 target genes <jats:italic>ASNS, ALDH1L2, MTHFD2, DDIT3<\/jats:italic> (<jats:italic>CHOP<\/jats:italic>), <jats:italic>DDIT4, TRIB3, EIF4EBP1, SLC7A11<\/jats:italic>, and <jats:italic>PPP1R15A<\/jats:italic> (<jats:italic>GADD34<\/jats:italic>). Transcript profiling and metabolomics analyses show that activated hypoxia\u2010inducible factor\u20101\u03b1 (HIF1\u03b1) signaling in our TRACK ccRCC murine model also induces an ATF4\u2010mediated ISR. Notably, both normoxic HIF1\u03b1 signaling in TRACK kidneys and VAD in wild\u2010type kidneys diminish amino acid levels, increase <jats:italic>ASNS, TRIB3<\/jats:italic>, and <jats:italic>MTHFD2<\/jats:italic> messenger RNA levels, and increase levels of lipids and GSH. By metabolic isotope tracing in human RCC4 kidney cancer parental and ATF4 gene\u2010edited (ATF4\u2010KO) cell lines, we show that ATF4 increases GSH accumulation in part via activation of the mitochondrial one\u2010carbon metabolism pathway. Our results demonstrate for the first time that activation of ATF4 enhances GSH accumulation, increases purine and pyrimidine biosynthesis, and contributes to transcriptional and metabolic remodeling in ccRCC. Moreover, constitutive HIF1\u03b1 expressed only in murine kidney proximal tubules activates ATF4, leading to the metabolic changes associated with the ISR. Our data indicate that HIF1\u03b1 can promote ccRCC via ATF4 activation. Moreover, lack of Vitamin A in the kidney recapitulates aspects of the ISR.<\/jats:p>","DOI":"10.1002\/mc.23437","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T08:23:17Z","timestamp":1655799797000},"page":"851-864","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Transcriptional and metabolic remodeling in clear cell renal cell carcinoma caused by ATF4 activation and the integrated stress response (ISR)"],"prefix":"10.1002","volume":"61","author":[{"given":"Johannes C.","family":"van der Mijn","sequence":"first","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medicine New York New York 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