2001 - Ph.D.
My lab has two major research interests: (1) Understanding the roles of Tumor Necrosis Factor (TNF)-α and Transforming Growth Factor (TGF)-β1 in radiation-induced lung toxicity to develop a strategy of lung radioprotection. (2) Exploring the roles of ubiquitination in cancer development and identify novel therapeutic targets.
(1) Radiotherapy in the treatment of thoracic cancers including lung cancer is restricted mainly due to the lung toxicity arises post-treatment. The main goal of this research proposal is to better understand the molecular regulators involved in radiation-induced lung toxicity and to develop improved agents that provide lung protection during radiotherapy and radio-chemotherapy. More specifically the current project is focused on improving our understanding about the involvements of TNF-a and TGF-b1 in radiation-induced lung toxicity and to develop strategies, which can block both the signaling pathways with expected better protection during lung cancer radio-chemotherapy.
(2) Accumulation of oncogene-specific activating mutation undoubtedly plays a key role not only in cancer initiation and progression, but in many occasions further promote drug resistance. In our laboratory we focus on studying the activating mutations in two important oncogenes: epidermal growth factor receptor (EGFR) and KRAS. Recently, we have obtained data that ubiquitination on mutant EGFR enhance its protein stability to develop drug resistance. Similarly, ubiquitin ligase activity also promotes mutant KRAS stability and GTPase activity, thus probably contributes towards drug-resistance. Our long-term objective is to identify the detailed ubiquitination machinery involved in maintaining mutant oncogene protein stability and further develop a novel strategy via targeting the ubiquitin ligase to kill oncogene-addicted tumors to overcome drug-resistance.
1. Ray D, Cuneo K, Lawrence TS, Nyati MK (2015) Inducing oncoprotein degradation to improve targeted cancer therapy. Neoplasia. In press.
2. Cuneo K, Nyati MK, Ray D, Lawrence TS (2015) EGFR targeted therapies and radiation optimization efficacy by appropriate drug scheduling and patient selection. Pharmacol. & Therapeutics. 154: 67-77. PMCID: PMC4570853.
3. Gillam MP, Nimbalkar D, Sun L, Christov K, Ray D, et al. (2015) MEN1 tumorigenesis in the pituitary and pancreatic islet requires CDK4, but not CDK2. Oncogene. 34(7):932-8. PMCID: PMC4135037
4. Ahsan A, Ramanand SG, Whitehead C, Hiniker SM, Rehemtulla A, Pratt WB, Jolly S, Gouveia C, Truong K, Van Waes C, Ray D, Lawrence TS, Nyati MK. Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors. Neoplasia. 2012 Aug;14(8):670-7. PMID:22952420
2. Ray D, Ahsan A, Helman A, Chen G, Hegde A, Gurjar SR, Zhao L, Kiyokawa H, Beer DG, Lawrence TS, Nyati MK (2011) Regulation of EGFR protein stability by the HECT-type ubiquitin ligase SMURF2. Neoplasia 2011 July;13(7):570-578. PMID 21750651.
3. Moore FE, Osmundson EC, Koblinski J, Pugacheva E, Golemis EA, Ray D, Kiyokawa H. The WW-HECT protein Smurf2 interacts with the Docking Protein NEDD9/HEF1 for Aurora A activation. Cell Division. 5:22, 2010. PMID: 2082567
4. Osmundson EC, Ray D, Moore F, Gao Q, Thomsen GH, Kiyokawa H. The HECT-domain E3 ligase is required for Mad2-dependent spindle assembly checkpoint and mitotic pro-gression. J Cell Biol 183(2):267-77, 2008. PMID: 18852296
5. Ray D, Osmundson EC, Kiyokawa H. Constitutive and UV-induced fibronectin degradation is a ubiquitination-dependent process controlled by β-TrCP. J Biol Chem 281(32): 23060-23065, 2006. PMID: 16757476
6. Ray D, Terao, Y, Nimbalkar D, Chu LH, Donzelli M, Tsutsui T, Zou X, Ghosh AK, Varga J, Draetta GF, Kiyokawa H. TGF-β facilitates β-TrCP-mediated degradation of Cdc25A in a Smad3-dependent manner. Mol Cell Biol 25 (8):3338-3347, 2005. PMID: 15798217
7. Ray D, Terao Y, Christov K, Kaldis P, Kiyokawa H. Cdk2-null mice are resistant to ErbB2-induced mammary tumorigenesis. Neoplsia 13(5): 439-444, 2011. PMID: 21532884