MTOR-Dependent Cell Proliferation in the Brain.

Larisa Ryskalin,Stefano Gambardella,Gloria Lazzeri,Francesca Biagioni,Alessandro Frati,Francesco Fornai,Marina Flaibani

doi:10.1155/2017/7082696

Larisa Ryskalin, Stefano Gambardella + Show 5 more

Open Access

https://doi.org/10.1155/2017/7082696

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Abstract

The mammalian Target of Rapamycin (mTOR) is a molecular complex equipped with kinase activity which controls cell viability being key in the PI3K/PTEN/Akt pathway. mTOR acts by integrating a number of environmental stimuli to regulate cell growth, proliferation, autophagy, and protein synthesis. These effects are based on the modulation of different metabolic pathways. Upregulation of mTOR associates with various pathological conditions, such as obesity, neurodegeneration, and brain tumors. This is the case of high-grade gliomas with a high propensity to proliferation and tissue invasion. Glioblastoma Multiforme (GBM) is a WHO grade IV malignant, aggressive, and lethal glioma. To date, a few treatments are available although the outcome of GBM patients remains poor. Experimental and pathological findings suggest that mTOR upregulation plays a major role in determining an aggressive phenotype, thus determining relapse and chemoresistance. Among several activities, mTOR-induced autophagy suppression is key in GBM malignancy. In this article, we discuss recent evidence about mTOR signaling and its role in normal brain development and pathological conditions, with a special emphasis on its role in GBM.

Highlights

The mammalian Target of Rapamycin is a 289-kDa serine/threonine kinase which belongs to the PI3K-related kinase (PIKK) family
The mammalian Target of Rapamycin is a molecular complex equipped with kinase activity which controls cell viability being key in the PI3K/PTEN/Akt pathway. mTOR acts by integrating a number of environmental stimuli to regulate cell growth, proliferation, autophagy, and protein synthesis
Nutrient availability, cellular energy status, growth factors, and other extracellular and environmental stimuli may activate mTORC1, which in turn acts on protein synthesis through a wide number of downstream substrates and in particular on the molecules of the translational machinery responsible for the recruitment of mRNA (4E-BP1, p7026K, and S6 ribosomal protein) [13, 25, 26]. mTORC1 is involved in regulating lipid biogenesis which is necessary for cell membrane generation and cell growth and proliferation

Summary

Molecular Structure and Functions of mTOR

The mammalian Target of Rapamycin (mTOR) is a 289-kDa serine/threonine kinase which belongs to the PI3K-related kinase (PIKK) family. This protein is the target of a molecule named rapamycin, a lipophilic macrolide compound produced by the bacterium Streptomyces hygroscopicus, which was isolated for the first time in the 1970s in a soil sample from Easter Island (Rapa Nui in Polynesian) [2, 3] This kinase plays a pivotal role in cell growth and metabolism acting as a key sensor and integrator of a variety of intra- and extracellular stimuli encompassing nutrients, growth factors, and energetic status and it represents a downstream substrate of PI3K/PTEN/Akt pathway, which controls protein synthesis and gene transcription, proliferation, and motility [4,5,6]. MTOR is activated by a large number of growth factors encompassing

Cell survival proliferation

Migration Tissue invasion Proliferation

Findings

Summary