{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:28:19Z","timestamp":1793165299965,"version":"4.5.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"46","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2014,11,18]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Despite the discovery of the von Hippel\u2013Lindau (\n                    <jats:italic>VHL<\/jats:italic>\n                    ) gene in 1993, and that inactivating germ-line mutations of\n                    <jats:italic>VHL<\/jats:italic>\n                    cause multiple kidney lesions, including clear-cell renal cell carcinoma (ccRCC),\n                    <jats:italic>Vhl<\/jats:italic>\n                    inactivation in the mouse does not lead to ccRCC and a mouse model has been lacking. We discovered that the BRCA1-associated protein-1 (\n                    <jats:italic>BAP1<\/jats:italic>\n                    ) two-hit tumor suppressor gene is mutated in ccRCC, and one\n                    <jats:italic>BAP1<\/jats:italic>\n                    allele is frequently somatically codeleted with\n                    <jats:italic>VHL<\/jats:italic>\n                    in tumors. In the mouse,\n                    <jats:italic>Vhl<\/jats:italic>\n                    and\n                    <jats:italic>Bap1<\/jats:italic>\n                    are on different chromosomes. We show that SIX homeobox 2 (\n                    <jats:italic>Six2<\/jats:italic>\n                    )\n                    <jats:italic>-Cre;Vhl<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>F\/F<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>;Bap1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>F\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    mice develop premalignant lesions and malignant ccRCC resembling VHL syndrome. More broadly, differences in tumor predisposition across species may result from differences in the location of two-hit tumor suppressor genes across the genome.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1414789111","type":"journal-article","created":{"date-parts":[[2014,10,30]],"date-time":"2014-10-30T23:28:44Z","timestamp":1414711724000},"page":"16538-16543","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":141,"title":["<i>Bap1<\/i>\n                    is essential for kidney function and cooperates with\n                    <i>Vhl<\/i>\n                    in renal tumorigenesis"],"prefix":"10.1073","volume":"111","author":[{"given":"Shan-Shan","family":"Wang","sequence":"first","affiliation":[{"name":"Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;"},{"name":"Departments of bDevelopmental Biology,"},{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Feng","family":"Gu","sequence":"additional","affiliation":[{"name":"Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;"},{"name":"Departments of bDevelopmental Biology,"},{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Wolff","sequence":"additional","affiliation":[{"name":"Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;"},{"name":"Departments of bDevelopmental Biology,"},{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoliina","family":"Stefanius","sequence":"additional","affiliation":[{"name":"Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;"},{"name":"Departments of bDevelopmental Biology,"},{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alana","family":"Christie","sequence":"additional","affiliation":[{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwesha","family":"Dey","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology, Genentech, South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Hammer","sequence":"additional","affiliation":[{"name":"Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-Jin","family":"Xie","sequence":"additional","affiliation":[{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Rakheja","sequence":"additional","affiliation":[{"name":"Pathology,"},{"name":"Pediatrics,"},{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Pedrosa","sequence":"additional","affiliation":[{"name":"Radiology, and"},{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;"},{"name":"Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; 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