Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation.
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 (RIP-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 MyrAkt1-mediated phenotype, we 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. 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.
Alliouachene
Samira
S
INSERM U845, Paris, France.
Tuttle
Robyn L
RL
Boumard
Stephanie
S
Lapointe
Thomas
T
Berissi
Sophie
S
Germain
Stephane
S
Jaubert
Francis
F
Tosh
David
D
Birnbaum
Morris J
MJ
Pende
Mario
M
D000818:Animals; D048429:Cell Size; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases