Email this page

Print this page

Extra Views

Double trouble: When Sonic hedgehog signaling meets TSC inactivation

Bobby Bhatia, Zaher Nahlé and Anna Marie Kenney

Certain types of medulloblastoma, the most common solid pediatric cancer, are proposed to arise from neural precursors known as cerebellar granule neuron precursors (CGNPs), which require signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) for their proliferation and survival. Aberrant activity of these pathways is implicated in medulloblastoma. IGF activates the mammalian Target of Rapamycin (mTOR), a growth-promoting kinase normally kept in check by the tumor suppressive Tuberous Sclerosis Complex (TSC), comprised of TSC1 and TSC2. TSC also counteracts proliferation by stabilizing the cyclin-dependent kinase inhibitor p27Kip1, preventing progression through G1- to S-phase of the cell cycle. We reported that mice with impaired TSC activity show increased susceptibility to Shh-mediated medulloblastoma. CGNPs and tumors from these mice display increased proliferation, mTOR pathway activation, glycogen synthase kinase-3 (GSK-3) α/β inactivation, and atypical p27Kip1 cytoplasmic localization. GSK-3α/β inactivation was mTOR-dependent, whereas p27Kip1 localization was uncoupled from mTOR, and was instead regulated by TSC2. These results provide insight into the molecular ‘hardwiring’ of the mitogenic network downstream of Shh signaling and emphasize the separate yet synergistic effects regulated by the TSC complex in (i) fueling proliferation through mTOR activation/GSK-3α/β inactivation and (ii) compromising checkpoint mechanisms via TSC2-dependent p27Kip1 nuclear exclusion. Future medulloblastoma therapies targeting Shh signaling can be developed to selectively modulate these activities, to restore checkpoint control and attenuate uncontrolled hyperproliferation.

Authors

Bobby Bhatia

Memorial Sloan-Kettering Cancer Center; New York, NY

Zaher Nahlé

Weill Cornell Medical College; New York, NY

Anna Marie Kenney Corresponding author: kenneya@mskcc.org

Memorial Sloan-Kettering Cancer Center; New York, NY