Inhibition of Akt kinase activity by a peptide spanning the betaA strand of the proto-oncogene TCL1.

Abstract	Akt plays a central role in the regulation of cellular anti-apoptosis underlying various human neoplastic diseases. We have demonstrated previously that TCL1 (a proto-oncogene underlying human T cell prolymphocytic leukemia) interacts with Akt and functions as an Akt kinase co-activator. With the aim to develop an Akt kinase inhibitor, we hypothesized that a peptide, which spans the Akt-binding site, binds to Akt and modulates Akt kinase activity and its downstream biological responses. Indeed, we demonstrated that a peptide, named "Akt-in" (Akt inhibitor, NH(2)-AVTDHPDRLWAWEKF-COOH, encompassing the betaA strand of human TCL1), interacted with Akt and specifically inhibited its kinase activity. Nuclear magnetic resonance studies suggested that interaction of Akt-in with the pleckstrin homology domain (PH) of Akt caused conformational changes on the variable loop 1 of Akt, the locus mediating phosphoinositide binding. Consistently, interaction of Akt-in with the Akt PH domain prevented phosphoinositide binding and hence inhibited membrane translocation and activation of Akt. Moreover, Akt-in inhibited not only cellular proliferation and anti-apoptosis in vitro but also in vivo tumor growth without any adverse effect. The roles of Akt, which possesses a PH domain, in intracellular signaling were well established. Hence, Akt inhibitors create an attractive target for anticancer therapy. However, no effective inhibitors specific for Akt have been developed. Akt-in, which inhibits association of phosphatidylinositol with Akt, is the first molecule to demonstrate specific Akt kinase inhibition potency. This observation will facilitate the design of specific inhibitors for Akt, a core intracellular survival factor underlying various human neoplastic diseases.
Authors	Makoto Hiromura, Futoshi Okada, Toshiyuki Obata, Daniel Auguin, Takeshi Shibata, Christian Roumestand, Masayuki Noguchi
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 51 Pg. 53407-18 (Dec 17 2004) ISSN: 0021-9258 [Print] United States
PMID	15459205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Blood Proteins Enzyme Inhibitors MAS1 protein, human Peptides Phosphatidylinositols Phosphoproteins Proto-Oncogene Mas Proto-Oncogene Proteins TCL1A protein, human platelet protein P47 Glutathione Transferase AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Topics	Amino Acid Sequence Animals Antineoplastic Agents (pharmacology) Apoptosis Binding, Competitive Blood Proteins (chemistry) Cell Line Cell Line, Tumor Cell Membrane (metabolism) Cell Proliferation Dose-Response Relationship, Drug Enzyme Inhibitors (pharmacology) Glutathione Transferase (metabolism) Humans Immunoprecipitation Kinetics Lipid Metabolism Magnetic Resonance Spectroscopy Mice Mice, Inbred C57BL Microscopy, Fluorescence Mitochondria (metabolism) Models, Molecular Molecular Sequence Data Neoplasm Transplantation Neoplasms (metabolism) Peptides (chemistry, pharmacology) Permeability Phosphatidylinositols (metabolism) Phosphoproteins (chemistry) Phosphorylation Protein Binding Protein Conformation Protein Serine-Threonine Kinases (antagonists & inhibitors) Protein Structure, Tertiary Protein Transport Proto-Oncogene Mas Proto-Oncogene Proteins (antagonists & inhibitors, chemistry, physiology) Proto-Oncogene Proteins c-akt Sequence Homology, Amino Acid Time Factors

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