Tuberous sclerosis complex (TSC) is a genetic disorder that results in sufferers developing benign tumors in many parts of their body. It is caused by genetic mutation of either of two genes, TSC1 or TSC2. The proteins encoded by these genes are negative regulators of a signaling pathway that is initiated at the cell surface by a ligand binding to PDGFR and that involves activation of PI3K, AKT, and mTOR.
The fact that individuals with TSC develop only benign tumors is somewhat surprising because genetic mutations that cause increased PDGFR, PI3K, and AKT activity are associated with malignant cancer, as are inactivating genetic mutations of other negative regulators of this signaling pathways (including PTEN).
In a study appearing online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, researchers from the Chinese Academy of Medical Sciences and Peking Union Medical College, People’s Republic of China, use mouse models of TSC to provide a potential explanation for the fact that individuals with TSC develop only benign tumors.
The lack of malignant tumors in mice expressing decreased levels of TSC1 or TSC2 is associated with decreased PDGFR expression and decreased PI3K and AKT activity, despite increased mTOR activity. Hongbing Zhang and colleagues now show that in mouse cell lines, activation of PI3K or AKT, as well as inhibition of PTEN, results in decreased PDGFR expression and negative feedback to dampen AKT activity, despite increased mTOR activity.
Furthermore, inhibiting mTOR restored PDGFR expression levels and AKT activity in mouse cell lines expressing decreased levels of TSC1 or TSC2, and overexpression of active AKT or PDGFR in such cells rendered them able to induce malignant tumors when transplanted into immunocompromised mice.
This study therefore demonstrates that increased mTOR activity decreases PDGFR expression and AKT activity in mouse cells expressing decreased levels of TSC1 or TSC2. More importantly, it offers a potential explanation for the observation that humans expressing mutant forms of TSC1 or TSC2 develop only benign tumors.
Materials provided by Journal of Clinical Investigation. Note: Content may be edited for style and length.
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