{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:44:31Z","timestamp":1791301471364,"version":"4.1.0"},"reference-count":31,"publisher":"Cold Spring Harbor Laboratory","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Dev."],"published-print":{"date-parts":[[2005,8,1]]},"abstract":"<jats:p>The role of tumor suppressor haploinsufficiency in oncogenesis is still poorly understood. The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of<jats:italic>Pten<\/jats:italic>and<jats:italic>Tsc2<\/jats:italic>in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner. In contrast, we found that while<jats:italic>Tsc2<\/jats:italic>heterozygosity unmasks<jats:italic>Pten<\/jats:italic>haploinsufficiency in growth and tumor suppression, tumorigenesis in<jats:italic>Tsc2<\/jats:italic><jats:sup>+\/-<\/jats:sup>mutants is surprisingly not accelerated by<jats:italic>Pten<\/jats:italic>heterozygosity, even though mTOR activation is cooperatively enhanced by compound<jats:italic>Pten\/Tsc2<\/jats:italic>heterozygosity. We show that the wild-type alleles of both<jats:italic>Pten<\/jats:italic>and<jats:italic>Tsc2<\/jats:italic>are retained in prostate tumors from both<jats:italic>Pten<\/jats:italic><jats:sup>+\/-<\/jats:sup>and<jats:italic>Pten<\/jats:italic><jats:sup>+\/-<\/jats:sup>Tsc2<jats:sup>+\/-<\/jats:sup>mice, whereas TSC-related tumor lesions are invariably associated with<jats:italic>Tsc2<\/jats:italic>loss of heterozygosity (LOH) in both<jats:italic>Tsc2<\/jats:italic><jats:sup>+\/-<\/jats:sup>and<jats:italic>Pten<\/jats:italic><jats:sup>+\/-<\/jats:sup>Tsc2<jats:sup>+\/-<\/jats:sup>mice. These findings demonstrate that inactivation of<jats:italic>TSC2<\/jats:italic>is epistatic to<jats:italic>PTEN<\/jats:italic>in the control of tumor initiation and progression and, importantly, that both<jats:italic>Pten<\/jats:italic>and<jats:italic>Tsc2<\/jats:italic>are haploinsufficient for suppression of tumorigenesis initiated by<jats:italic>Pten<\/jats:italic>heterozygosity, while neither<jats:italic>Pten<\/jats:italic>nor<jats:italic>Tsc2<\/jats:italic>is haploinsufficient for repression of carcinogenesis arising from<jats:italic>Tsc2<\/jats:italic>heterozygosity, providing a rationale for the differential cancer susceptibility of the two human conditions associated with<jats:italic>PTEN<\/jats:italic>or<jats:italic>TSC2<\/jats:italic>heterozygous mutations.<\/jats:p>","DOI":"10.1101\/gad.1314405","type":"journal-article","created":{"date-parts":[[2005,7,19]],"date-time":"2005-07-19T00:24:43Z","timestamp":1121732683000},"page":"1779-1786","source":"Crossref","is-referenced-by-count":96,"title":["Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression"],"prefix":"10.1101","volume":"19","author":[{"given":"Li","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Teruya-Feldstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nille","family":"Behrendt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenbang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Okio","family":"Hino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cordon-Cardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Paolo","family":"Pandolfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[2005,7,18]]},"reference":[{"key":"2021111607300529000_19.15.1779.1","first-page":"4997","volume":"57","year":"1997","journal-title":"Cancer Res."},{"key":"2021111607300529000_19.15.1779.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.8.4240"},{"key":"2021111607300529000_19.15.1779.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80674-1"},{"key":"2021111607300529000_19.15.1779.4","doi-asserted-by":"publisher","DOI":"10.1038\/1235"},{"key":"2021111607300529000_19.15.1779.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5436.2122"},{"key":"2021111607300529000_19.15.1779.6","doi-asserted-by":"publisher","DOI":"10.1038\/84879"},{"key":"2021111607300529000_19.15.1779.7","doi-asserted-by":"publisher","DOI":"10.1101\/gad.887201"},{"key":"2021111607300529000_19.15.1779.8","doi-asserted-by":"crossref","unstructured":"Gomez M.R ., Sampson, J.R., and Whittemore, V.H. 1999. 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