Mammalian target of rapamycin: Master regulator of cell growth in the nervous system
D.K. Sandsmark1,2, C. Pelletier3,4, J.D. Weber3,4 and D.H. Gutmann1,2
Departments of 1Neurology, 2Neuroscience, 3Cell Biology and 4Molecular Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Offprint requests to: David H. Gutmann, MD, PhD, Department of Neurology, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, MO 63110. USA. e-mail: gutmannd@ wustl.edu
Summary. The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our current understanding of the mTOR signaling pathway and its role in promoting ribosome biogenesis and cell growth. We suggest that studies of this pathway may prove useful in identifying molecular targets for biologically-based therapies of brain tumors associated with these inherited cancer syndromes as well as sporadic central nervous system tumors. Histol Histopathol 22, 895-903 (2007)
Key words: mTOR, NF1, TSC, PEN, Rapamycin