{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T20:04:57Z","timestamp":1778875497753,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UC Tobacco-Related Disease Research Program","award":["27IP-0016"],"award-info":[{"award-number":["27IP-0016"]}]},{"name":"UC Tobacco-Related Disease Research Program","award":["W81XWH-20-1-0918"],"award-info":[{"award-number":["W81XWH-20-1-0918"]}]},{"name":"UC Tobacco-Related Disease Research Program","award":["HT94252310858"],"award-info":[{"award-number":["HT94252310858"]}]},{"name":"CDMRP Kidney Cancer Research Program","award":["27IP-0016"],"award-info":[{"award-number":["27IP-0016"]}]},{"name":"CDMRP Kidney Cancer Research Program","award":["W81XWH-20-1-0918"],"award-info":[{"award-number":["W81XWH-20-1-0918"]}]},{"name":"CDMRP Kidney Cancer Research Program","award":["HT94252310858"],"award-info":[{"award-number":["HT94252310858"]}]},{"name":"Kure It Foundation","award":["27IP-0016"],"award-info":[{"award-number":["27IP-0016"]}]},{"name":"Kure It Foundation","award":["W81XWH-20-1-0918"],"award-info":[{"award-number":["W81XWH-20-1-0918"]}]},{"name":"Kure It Foundation","award":["HT94252310858"],"award-info":[{"award-number":["HT94252310858"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the current era of tumor genome sequencing, single amino acid missense variants in the von Hippel\u2013Lindau (VHL) tumor suppressor gene are frequently identified in clear cell renal carcinoma (ccRCC). Due to the incomplete knowledge of the structural architecture of VHL protein, the functional significance of many missense mutations cannot be assigned. L169P is one such missense mutation identified in the case of aggressive, metastatic ccRCC. Here, we characterized the biochemical activity, transcriptomic hypoxia signature and biological functions of the L169P variant. Lentiviral vector expressing either wildtype (WT) or L169P VHL were used to transduce two VHL-deficient human ccRCC cell lines, 786-O and RCC4. The stability of the VHL protein and the expression level of VHL, HIF1\u03b1 and HIF2\u03b1 were analyzed. The impact of restoring L169P or WT VHL on the hypoxia gene expression program in 786-O cells was assessed by mRNA sequencing (RNAseq) and computed hypoxic scores. The impact of restoring VHL expression on the growth of ccRCC models was assessed in cell cultures and in chorioallantoic membrane (CAM) xenografts. In the 786-O cells, the protein stability of L169P VHL was comparable to WT VHL. No obvious difference in the capability of degrading HIF1\u03b1 and HIF2\u03b1 was observed between WT and L169P VHL in the 786-O or RCC4 cells. The hypoxic scores were not significantly different in the 786-O cells expressing either wildtype or L169P VHL. From the cellular function perspective, both WT and L169P VHL slowed cell proliferation in vitro and in vivo. The L169P VHL variant is comparable to WT VHL in terms of protein stability, ability to degrade HIF1\u03b1 factors and ability to regulate hypoxia gene expression, as well as in the suppression of ccRCC tumor cell growth. Taken together, our data indicate that the L169P VHL variant alone is unlikely to drive the oncogenesis of sporadic ccRCC.<\/jats:p>","DOI":"10.3390\/ijms241814075","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T09:57:56Z","timestamp":1694685476000},"page":"14075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["VHL L169P Variant Does Not Alter Cellular Hypoxia Tension in Clear Cell Renal Cell Carcinoma"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9260-2858","authenticated-orcid":false,"given":"Junhui","family":"Hu","sequence":"first","affiliation":[{"name":"Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA"},{"name":"Institute of Urologic Oncology, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Desmond J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA"},{"name":"Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lily","family":"Wu","sequence":"additional","affiliation":[{"name":"Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA"},{"name":"Institute of Urologic Oncology, University of California Los Angeles, Los Angeles, CA 90095, USA"},{"name":"Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.semcancer.2012.06.003","article-title":"Genomics and epigenomics of renal cell carcinoma","volume":"23","author":"Maher","year":"2013","journal-title":"Semin. 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