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Review|Volume 3, Issue 3|pp 192—222

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

Linda S. Steelman1,2, William H. Chappell1, Stephen L. Abrams1, C. Ruth Kempf2, Jacquelyn Long2, Piotr Laidler3, Sanja Mijatovic4, Danijela Maksimovic-Ivanic4, Franca Stivala5, Maria C. Mazzarino5, Marco Donia5, Paolo Fagone5, Graziella Malaponte5, Ferdinando Nicoletti5, Massimo Libra5, Michele Milella6, Agostino Tafuri7, Antonio Bonati8, Jörg Bäsecke9, Lucio Cocco10, Camilla Evangelisti10, Alberto M. Martelli10,11, Giuseppe Montalto12, Melchiorre Cervello13, James A. McCubrey1
  • 1Department of Microbiology and Immunology, East Carolina University, Greenville, NC 27858, USA
  • 2Department of Physics, East Carolina University, Greenville, NC 27858, USA
  • 3Department of Medical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
  • 4Department of Immunology, Instititue for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia
  • 5Department of Biomedical Sciences, University of Catania, Catania, Italy
  • 6Regina Elena Cancer Center, Rome 00144, Italy
  • 7University of Rome, La Sapienza, Department of Hematology-Oncology, Rome 99161, Italy
  • 8University Hospital of Parma, Unit of Hematology and Bone-Marrow Transplantation, Via Gramsi n.14, Parma 43100, Italy
  • 9Department of Medicine, University of Göttingen, Göttingen, Germany
  • 10Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, Bologna, Italy
  • 11IGM-CNR, Sezione di Bologna, C/o IOR, Bologna, Italy
  • 12Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy
  • 13Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia, Molecolare “Alberto Monroy”, Palermo, Italy
Received: February 25, 2011Accepted: March 10, 2011Published: March 10, 2011

Copyright: © 2011 Steelman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health.