Study reported in the Journal of Clinical Investigation suggests that S6K1 is necessary for the Akt pathway to lead to insulinoma.

Researchers working to determine the role of the protein Akt1 in regulating the growth and function of mouse pancreatic â cells discovered that a number of mice died after developing insulinomas, a rare form of pancreatic cancer.

Further analysis revealed that the signaling protein S6 kinase 1 (S6K1) was required for constitutively activated Akt to trigger insulinoma formation but was not required for it to increase pancreatic â size.

Factors that promote pancreatic â-cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggested that signaling cascades initiated by insulin and IGFs positively regulate â cell mass and insulin secretion. Akt and S6K family members are activated as part of these signaling cascades, but how these proteins control â-cell growth and function had not been determined.

In this study, investigators found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged â cells and high plasma insulin levels leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life.

To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, the team crossed RIP-MyrAkt1 and S6K1-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.

Although the increase in â-cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. This data imply that S6K1 is a critical element for MyrAkt1-induced tumor formation.

The findings appears in the Journal of Clinical Investigation. Researchers working on the study are from INSERM U845 and a number of other medical institutions.

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