Targeting mTOR as a novel therapeutic strategy for traumatic CNS injuries.

The adult central nervous system (CNS) has a remarkable ability to repair itself. However, severe brain and spinal cord injuries (SCIs) cause lasting disability and there are only a few therapies that can prevent or restore function in such cases. In this review, we provide an overview of traumatic CNS injuries and discuss several emerging pharmacological options that have shown promise in preclinical and early clinical studies. We highlight therapies that modulate mammalian target of rapamycin (mTOR) signaling, a pathway that is well known for its roles in cell growth, metabolism and cancer. Interestingly, this pathway is also gaining newfound attention for its role in CNS repair and regeneration.

Recent clinical trials of mTOR-targeted cancer therapies.

The mammalian target of rapamycin (mTOR) is a central component within a complex intracellular signaling network that regulates various processes including cell growth, proliferation, metabolism, and angiogenesis. A hyperactive PI3k/Akt/mTOR signaling pathway is found in many human cancers and alterations in this pathway is associated with the development and progression of cancer. Drugs that target and inhibit mTOR activity are therefore expected to provide therapeutic value in a number of cancer types. Several classes of mTOR-targeted therapeutics are currently being evaluated in cancer clinical trials, including the rapamycins, dual PI3K-mTOR inhibitors, and ATP-competitive mTORC1/2 inhibitors. This review summarizes important findings from recently completed trials of mTOR inhibitors and also discusses preliminary data from ongoing trials.

Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest.

Cyclin G2, together with cyclin G1 and cyclin I, defines a novel cyclin family expressed in terminally differentiated tissues including brain and muscle. Cyclin G2 expression is up-regulated as cells undergo cell cycle arrest or apoptosis in response to inhibitory stimuli independent of p53 (Horne, M., Donaldson, K., Goolsby, G., Tran, D., Mulheisen, M., Hell, J. and Wahl, A. (1997) J. Biol. Chem. 272, 12650-12661). We tested the hypothesis that cyclin G2 may be a negative regulator of cell cycle progression and found that ectopic expression of cyclin G2 induces the formation of aberrant nuclei and cell cycle arrest in HEK293 and Chinese hamster ovary cells. Cyclin G2 is primarily partitioned to a detergent-resistant compartment, suggesting an association with cytoskeletal elements. We determined that cyclin G2 and its homolog cyclin G1 directly interact with the catalytic subunit of protein phosphatase 2A (PP2A). An okadaic acid-sensitive (<2 nm) phosphatase activity coprecipitates with endogenous and ectopic cyclin G2. We found that cyclin G2 also associates with various PP2A B' regulatory subunits, as previously shown for cyclin G1. The PP2A/A subunit is not detectable in cyclin G2-PP2A-B'-C complexes. Notably, cyclin G2 colocalizes with both PP2A/C and B' subunits in detergent-resistant cellular compartments, suggesting that these complexes form in living cells. The ability of cyclin G2 to inhibit cell cycle progression correlates with its ability to bind PP2A/B' and C subunits. Together, our findings suggest that cyclin G2-PP2A complexes inhibit cell cycle progression.