Mechanisms And Biological Significances Of Up-regulation Of PTEN By Loss Of TSC1/TSC2Complex

Tuberous Sclerosis Complex (TSC) is a dominant autosomal inherited disease characterized by the formation of numorous benign tumors in a variety of organ systems. This disease is caused by mutations in either TSC1or TSC2tomor suppressor genes. The protein products of TSC1and TSC2assemble to form a protein complex which serves as a negative regulator of small G protein Rheb through its GTPase-activating protein activity. Rheb acts as a positive regulator of mTOR. Mutations in either TSC1or TSC2gene lead to loss of TSC1/TSC2complex function and in turn cause hyperactivation of mTOR and the uncontrollable cell growth and cell proliferation. The negative feedback inhibition of AKT by aberrantly activated mTOR, even though its underlying mechanisms remain elusive, is considered as an important contributor to the development of benign tumors in TSC patients.TSC1-/-MEFs and TSC2-/-MEFs are widely used as cell models for the study of mTOR signaling and related diseases. We found that the expression of PTEN increased significantly in TSC1-/-MEFs and TSC2-/-MEFs in comparison with control MEFs. Elevated expression of PTEN inhibits cell proliferation of TSC1-/-MEFs and TSC2-/-MEFs. Futhermore, hyperactivation of mTOR induced by inactivation of TSC1/TSC2complex enhances PTEN expression through activation of STAT3. Moreover, activated STAT3binds to a conserved STAT3binding site in PTEN promoter for the transcriptional up-regulation of PTEN gene. Based on these observations, we speculate that the increased PTEN expression caused by loss of TSC1/TSC2complex function help to explain why Tuberous Sclerosis Complex usually develops benign tumors.