Diagenode

Yin Yang 1 Deficiency in Skeletal Muscle Protects against Rapamycin-Induced Diabetic-like Symptoms through Activation of Insulin/IGF Signaling.


Blättler SM, Cunningham JT, Verdeguer F, Chim H, Haas W, Liu H, Romanino K, Rüegg MA, Gygi SP, Shi Y, Puigserver P

Rapamycin and its derivatives are mTOR inhibitors used in tissue transplantation and cancer therapy. A percentage of patients treated with these inhibitors develop diabetic-like symptoms, but the molecular mechanisms are unknown. We show here that chronic rapamycin treatment in mice led to insulin resistance with suppression of insulin/IGF signaling and genes associated within this pathway, such as Igf1-2, Irs1-2, and Akt1-3. Importantly, skeletal muscle-specific YY1 knockout mice were protected from rapamycin-induced diabetic-like symptoms. This protection was caused by hyperactivation of insulin/IGF signaling with increased gene expression in this cascade that, in contrast to wild-type mice, was not suppressed by rapamycin. Mechanistically, rapamycin induced YY1 dephosphorylation and recruitment to promoters of insulin/IGF genes, which promoted interaction with the polycomb protein-2 corepressor. This was associated with H3K27 trimethylation leading to decreased gene expression and insulin signaling. These results have implications for rapamycin action in human diseases and biological processes such as longevity.

Tags
Bioruptor
Chromatin Shearing
ChIP-qPCR

Share this article

Published
April, 2012

Source

活动

  • AACR 2024
    San Diego, California, USA
    Apr 5-Apr 10, 2024
 查看所有活动

新闻

 查看所有新闻


The European Regional Development Fund and Wallonia are investing in your future.

Extension of industrial buildings and new laboratories.


       Site map   |   Contact us   |   Conditions of sales   |   Conditions of purchase   |   Privacy policy   |   Diagenode Diagnostics