A loss of epigenetic control can promote cell death through reversing the balance of pathways in a signaling network
Description
Epigenetic loss of imprinting (LOI) of the Insulin Like Growth Factor -2 (IGF-2) results in an aberrant multicopy expression of IGF-2. This overexpression of IGF-2 results in an altered state of the Insulin like Growth Factor Receptor -1 (IGF1R) signaling network starting with an overexpression of IGF1R. We show that there is increased internalization of IGF1R upon stimulation by the ligand IGF2 resulting in an altered strength of activation of the downstream kinases Akt and Erk. While the strength of Akt signaling is comparitively decreased, the strength of Erk signaling is increased in the IGF2 LOI system. This altered strength of signaling of Akt and Erk kinases propagates to the level of anti and pro apoptotic determinants. This adjustment makes the LOI cells more vulnerable to inhibition of the IGF1R pathway although they still maintain a proliferative growth advantage. The data linked here is/ are the original blots of the data presented in the paper.
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Steps to reproduce
Most of the data can be reproduced by Western blotting of the lysates obtained from the mouse embryonic fibroblasts of the IGF2 LOI system. All the methodology are listed in the STAR methods .