THE PLAS LAB

David Plas's Lab
The Plas lab studies the regulation of cell metabolism, cell growth, and programmed cell death (or apoptosis), with an overarching interest in how these processes relate to diseases such as cancer, diabetes, and autoimmunity. Genetic studies have shown that the serine-threonine kinase Akt plays a pivotal role in coordinating cell size, metabolism, and survival in normal and cancerous tissues by antagonizing the function of tumor suppressor genes. Among the known Akt substrates are the TSC2 and FOXO tumor suppressor proteins. TSC2 is a regulator of cell size that is mutated in Tuberous Sclerosis, a syndrome characterized by a predisposition for tumor formation. FOXO proteins are transcription factors that can control cell size, survival, and metabolism. Our lab has shown that Akt phosphorylation of TSC2 and FOXO proteins targets them for degradation via the proteasome. This suggests that the oncogenic effects of Akt may be due to its ability to inactivate tumor suppressors and mark them for proteasomal destruction. The Plas lab is exploring this hypothesis and its corollaries using mouse genetics, proteomics, and cell culture model systems. Ongoing projects in the lab are directed at addressing the following specific issues: 1) the pathways downstream of Akt that coordinate cell size, metabolism, and survival; 2) the mechanism by which Akt induces degradation of its substrates; 3) the links between cell metabolism and the mitochondrial release of apoptotic factors; and 4) identification of new substrates in the Akt pathway.

Selected Publications:
Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology.J Biol Chem. 2001 Apr;276(15):12041-8.

Plas DR, Rathmell JC, Thompson CB. Homeostatic control of lymphocyte survival: potential origins and implications.Nat Immunol. 2002 Jun;3(6):515-21.

Plas DR, Thompson CB. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome.J Biol Chem. 2003 Apr;278(14):12361-6.

Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.Mol Cell. 2005 Apr;18(3):283-93.

Plas DR, Thompson CB. Akt-dependent transformation: there is more to growth than just surviving.Oncogene. 2005 Nov;24(50):7435-42.