期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 118, 期 11, 页码 3629-3638出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI35237
关键词
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资金
- INSERM Avenir [R01131KS]
- INSERM-Fondation pour la Recherche Medicale-Juvenile Diabetes Research Foundation International [4DA03H]
- Ligue Contre le Cancer
- Fondation de la Recherche Medicale [DEQ200611079S6]
- Fondation Schlumberger pour l'Education et la Recherche
Factors that promote pancreatic beta cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate beta cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls beta cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RTP-MyrAkt1 mice) had enlarged beta cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAktl-mediated phenotype, we crossed RIP-MyrAkt1 and S6W1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in beta cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR.
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