PI3K-Akt-mTOR Pathway Regulates Cell Differentiation

PI3K-Akt-mTOR signal pathway plays various roles in cell metabolism, proliferation, apoptosis, growth and differentiation. Malfunction of this pathway has been implicated in human cancer, inflammation, metabolism, and cardiovascular disease. Therefore, this pathway is regarded as one of the most important signaling pathways and is currently under intensive investigation.Aberrant cell differentiation can result in many disorders, such as cancer. Cancer is a differentiation defective disease. In the first part of this thesis, we investigated the relationship between mTOR signal pathway and cell differentiation. Multiple proto-oncogenes and tumor-suppressor genes in PI3K-Akt-mTOR signal pathway are frequently altered in tumors. Our experimental results show that over-activation of mTOR signal pathway suppresses cell differentiation, which is Notch dependent and through p63—Jagged-1—Notch cascade. Our findings may gain some insights into the mechanism of tumorigenesis and provide novel approaches for cancer therapy.In the second part of this thesis, we demonstrated that PDGFR, an important RTK in PI3K-Akt-mTOR signal pathway, contributes significantly to the regulation of insulin signaling through regulating IRS (insulin receptor substrates) which is pivot in the downstream of insulin pathway.In the third part of this thesis, we studied the effects of the activity of PI3K-Akt-mTOR signal pathway on the differentiation of MSCs (Mesenchymal stem cells) and murine 3T3-L1 preadiocyte cell line. The activation of mTOR signal pathway is required for the differentiation of murine 3T3-L1 preadiocyte cell line which is insulin-dependant. On the contrary, mTOR signal pathway is down-regulated during the differentiation of MSCs.