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Putting the Rap on Akt

From the Division of Hematology/Oncology, Department of Medicine, Department of Cancer Biology, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA

Address reprint requests to Craig B. Thompson, MD, University of Pennsylvania, Abramson Family Cancer Research Institute, 421 Curie Blvd, Room 450 BRB II/III, Philadelphia, PA 19104-6160; e-mail: craig{at}mail.med.upenn.edu

The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.

J.E.T. was supported by National Institutes of Health grants T32-HL07439-24 and K08-HL73977-01.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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