The insulin/IGF-IRS-PI3K-Akt pathway is highly conserved in evolution. To test whether this signaling cascade determines organ size in vertebrates, we have recently created mouse lines transgenic for constitutively active (caPI3K) and dominant-negative forms of PI3K (dnPI3K) (Shioi et al., 2000). Transgene expression is driven by the cardiac-specific a -myosin heavy chain (MHC) promoter. Both transgenic lines are characterized by moderate but highly consistent changes in heart size, despite the fact that body weight and the size of other organs are completely normal. caPI3K transgenic animals have hearts 20% larger than those of wild type littermates, whereas dnPI3K mice have hearts that are 17% smaller. The observed changes in heart size correlate with an appropriate increase or decrease in the size of transgenic cardiomyocytes. These hearts do not have cardiomyopathic changes, since the contractile function of transgenic hearts is normal, and signs of necrosis, apoptosis, or interstitial fibrosis are absent (see Physiology). These data suggest an autonomous role for PI3K in cell size regulation. Our goal is now to determine how activation of this system translates into changes in cell size by identifying the trigger and components of this signaling cascade. Heterozygous caPI3K (constitutively active PI3K) and dnPI3K (dominant-negative PI3K) transgenic female mice (5-14 months) compared with non-transgenic littermates. Transgene expression driven by the a -myosin heavy chain (a -MHC) promoter.
Nppa UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Rbm39 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Pah UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Pik3r1 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Myh7 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
(Factor value) GENOTYPE/wild type genotype
Phlda1 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Ctgf UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Bex1 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Myl1 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Ppara DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Wnk1 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Analysis of 'dominant-negative caPI3K transgenic' vs 'wild type'
Pten DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
(Sample) genotype/constitutively active caPI3K transgenic
Cpxm2 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Yam1 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Acta1 UP in 'constitutively active caPI3K transgenic' vs 'wild type'
Dynll2 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
(Sample) genotype/dominant-negative caPI3K transgenic
(Factor value) GENOTYPE/constitutively active caPI3K transgenic
Rab10 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Pah DOWN in 'constitutively active caPI3K transgenic' vs 'wild type'
(Factor value) GENOTYPE/dominant-negative caPI3K transgenic
Analysis of 'constitutively active caPI3K transgenic' vs 'wild type'
Gdap10 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Psap UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Myl4 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Tpm2 UP in 'dominant-negative caPI3K transgenic' vs 'wild type'
Hsph1 UP in 'constitutively active caPI3K transgenic' vs 'wild type'
Myl7 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'
Casq1 DOWN in 'dominant-negative caPI3K transgenic' vs 'wild type'