Plas Lab
2180 E. Galbraith Rd.
Cincinnati, OH 45237

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Publications

Regulation of programmed cell death, or apoptosis, is central to maintaining appropriate cell numbers within an organism. The serine/threonine kinase Akt can block apoptosis while simultaneously supporting increases in cellular metabolism and size. Alterations in Akt activation are associated with numerous disease states, including cancer, diabetes, premature aging, and obesity. Two major targets of Akt signal transduction are the tumor suppressors TSC2 and FOXO proteins. Work in the 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 mediated through its ability to inactivate tumor suppressors and mark them for proteasomal destruction.

Because Akt occupies a central point in coordinating cell size, metabolism, and survival, there is much interest in understanding how Akt activation contributes to the development of disease. The laboratory is using mouse genetics, proteomic studies, and cell culture model systems to investigate the hypothesis that Akt controls a cell’s metabolic program by inhibiting tumor suppressor genes, and thereby regulates the sensitivity of a cell to apoptosis. Specific studies include: 1) The pathways that coordinate cell size, metabolism and survival downstream of Akt. 2) The mechanism by which Akt induces degradation of its substrates. 3) The links between cell metabolism and the mitochondrial release of apoptogenic factors. 4) Identification of new substrates in the Akt pathway. The laboratory will use the results of these studies to design new approaches for the treatment of diseases such as diabetes, autoimmunity, and cancer.



Publications

1:	Plas DR, Thompson CB Akt-dependent transformation: there is more to growth than just surviving. Oncogene. 2005 Nov;24(50):7435-42. PMID: 16288290 [PubMed - indexed for MEDLINE]

2:	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. PMID: 15866171 [PubMed - indexed for MEDLINE]

3:	Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004 Jun;64(11):3892-9. PMID: 15172999 [PubMed - indexed for MEDLINE]

4:	Arsham AM, Plas DR, Thompson CB, Simon MC Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Res. 2004 May;64(10):3500-7. PMID: 15150104 [PubMed - indexed for MEDLINE]

5:	Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol. 2003 Oct;23(20):7315-28. PMID: 14517300 [PubMed - indexed for MEDLINE]

6:	Karnauskas R, Niu Q, Talapatra S, Plas DR, Greene ME, Crispino JD, Rudin CM Bcl-x(L) and Akt cooperate to promote leukemogenesis in vivo. Oncogene. 2003 Feb;22(5):688-98. PMID: 12569361 [PubMed - indexed for MEDLINE]

7:	Plas DR, Thompson CB Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem. 2003 Apr;278(14):12361-6. PMID: 12517744 [PubMed - indexed for MEDLINE]

8:	Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002 Jun;16(6):769-77. PMID: 12121659 [PubMed - indexed for MEDLINE]

9:	Plas DR, Rathmell JC, Thompson CB Homeostatic control of lymphocyte survival: potential origins and implications. Nat Immunol. 2002 Jun;3(6):515-21. PMID: 12032565 [PubMed - indexed for MEDLINE]

10:	Arsham AM, Plas DR, Thompson CB, Simon MC Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription. J Biol Chem. 2002 Apr;277(17):15162-70. PMID: 11859074 [PubMed - indexed for MEDLINE]

11:	Plas DR, Thompson CB Cell metabolism in the regulation of programmed cell death. Trends Endocrinol Metab. 2002 Mar;13(2):75-8. PMID: 11854022 [PubMed - indexed for MEDLINE]

12:	Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol. 2001 Sep;21(17):5899-912. PMID: 11486029 [PubMed - indexed for MEDLINE]

13:	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. PMID: 11278698 [PubMed - indexed for MEDLINE]

14:	Plas DR, Williams CB, Kersh GJ, White LS, White JM, Paust S, Ulyanova T, Allen PM, Thomas ML Cutting edge: the tyrosine phosphatase SHP-1 regulates thymocyte positive selection. J Immunol. 1999 May;162(10):5680-4. PMID: 10229799 [PubMed - indexed for MEDLINE]

15:

Dustin LB, Plas DR, Wong J, Hu YT, Soto C, Chan AC, Thomas ML Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation. J Immunol. 1999 Mar;162(5):2717-24. PMID: 10072516 [PubMed - indexed for MEDLINE]

16:	Wang LL, Blasioli J, Plas DR, Thomas ML, Yokoyama WM Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B. J Immunol. 1999 Feb;162(3):1318-23. PMID: 9973385 [PubMed - indexed for MEDLINE]

17:	Plas DR, Thomas ML Negative regulation of antigen receptor signaling in lymphocytes. J Mol Med. 1998 Jul;76(8):589-95. PMID: 9694436 [PubMed - indexed for MEDLINE]

18:	Matsumoto M, Lo SF, Carruthers CJ, Min J, Mariathasan S, Huang G, Plas DR, Martin SM, Geha RS, Nahm MH, Chaplin DD Affinity maturation without germinal centres in lymphotoxin-alpha-deficient mice. Nature. 1996 Aug;382(6590):462-6. PMID: 8684487 [PubMed - indexed for MEDLINE]

19:	Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, Chan AC, Thomas ML Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science. 1996 May;272(5265):1173-6. PMID: 8638162 [PubMed - indexed for MEDLINE]

20:	Moe AJ, Plas DR, Powell KA, Smith CH Riboflavin uptake in microvillous and basal membrane vesicles isolated from full-term human placentas. Placenta. ;15(2):137-46. PMID: 8008729 [PubMed - indexed for MEDLINE]