The PI3-Kinase/TSC Pathway: A Role in Neural and Renal Development and Pathology




Zhou, Jing

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PTEN is a tumor suppressor gene and its protein product negatively regulates the PI3K/AKT pathway through counteracting the kinase function of PI3-Kinase. Loss of function of PTEN results in overactivation of AKT and in turn activates multiple AKT downstream pathways. One AKT substrate is the TSC1/2 protein complex, which controls protein synthesis and cell growth through regulating mTOR activity. AKT inhibits TSC1/2 complex by directly phosphorylating TSC2, and in turn releases the inhibition of TSC1/2 complex on mTOR. Thus, loss of either PTEN or TSC1 or TSC2 can result in increased mTOR activity. However, regulation of TSC1/2 complex by AKT could be context dependent and the TSC/mTOR pathway is regulated by upstream regulators other than AKT in different cell types. In this study, I characterized the functions of PTEN and TSC1 in both post-mitotic neurons and renal tubule cells, and evaluated the relationship of these two tumor suppressor genes in two distinct contexts. Previously, a conditional Pten knockout mouse line was generated with Pten loss in limited post-mitotic neurons in the cortex and hippocampus. These mice develop macrocephaly accompanied by neuronal hypertrophy and loss of neuronal polarity. The mutant mice also exhibit behavioral abnormalities reminiscent of certain features of human autism. Biochemical analysis indicates that multiple AKT downstream pathways including the TSC/mTOR pathway are activated in neurons that lose Pten. In the current study, I demonstrate that rapamycin, a specific inhibitor of mTOR, can prevent or reverse neuronal hypertrophy resulting in the amelioration of PTEN-associated abnormal behaviors. In addition, loss of Tsc1 in a same context results in similar neuronal hypertrophy. Thus, the study provides evidence that the mTOR pathway is critical for the neuronal phenotype observed in Pten mutant mice. In the second part of the study, I demonstrate that severe polycystic kidneys disease develops in Tsc1 mutant mice, but not in Pten mutant mice. Apparently, overactivation of mTOR signaling only occurs in the kidneys of Tsc1 mutant mice, suggesting distinct activities for PTEN and TSC1 in mTOR activation in renal tubule cells compared to that found in neurons.

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