DF/HCC Program Affiliation

Kidney Cancer
Cancer Cell Biology

Research Abstract

Research in the Manning laboratory is aimed at characterizing biochemical links between cellular signaling pathways involved in tumor development and those controlling central metabolism. The goal of this research is to understand the role of oncogenes and tumor suppressors in coordinating cellular signaling events propagated by growth factors, the availability of energy and nutrients, and exposure to environmental stresses. The ability to properly perceive and integrate these signals at both the cellular and organismal levels is essential for the prevention of tumorigenesis and the maintenance of metabolic homeostasis. To elucidate the detailed mechanisms of pathways involved in these processes, the laboratory uses a multi-tiered approach involving bioinformatics, biochemistry, cell biology, genetics, and animal models. We are particularly interested in pathways controlling and controlled by the products of the tumor suppressor genes, TSC1 and TSC2, mutated in the disease tuberous sclerosis complex (TSC). TSC is a tumor syndrome severely affecting multiple organ systems including the brain, skin, kidney, lung, and heart. Our work in this field has helped uncover a molecular link between these tumor suppressors and control of the mammalian target of rapamycin (mTOR) by the PI3K-Akt pathway. Using cell and mouse models, we are investigating the contribution of this pathway to the many cancers exhibiting aberrant activation of the PI3K-Akt pathway.

Publications

• Huang J, Dibble CC, Matsuzaki M, Manning BD.The TSC1-TSC2 complex is required for proper activation of mTOR complex 2.Mol Cell Biol 2008 Apr 14.
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• Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, Hotamisligil GS.Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis.Mol Cell 2008 Mar 14;29(5):541-51.
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• Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD.S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt.Mol Cell 2006 Oct 20;24(2):185-97.
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• Manning BD,Logsdon MN,Lipovsky AI,Abbott D,Kwiatkowski DJ,Cantley LC.Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2.Genes Dev 2005 Aug 1;19(15):1773-8.
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• Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC.Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.Mol Cell 2002 Jul;10(1):151-62.
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