Myc is an oncoprotein transcription factor that features prominently in a variety of human cancers. Indeed, itis estimated that approximately one-third of all cancer deaths in the United States involve inappropriate Mycexpression or activity. Cells have evolved a number of mechanisms to restrict Myc expression in normalcells, one of which is ubiquitin (Ub)-mediated proteolysis. The importance of Myc destruction is evidenced bythe fact that cancer-associated mutations within Myc block its destruction and potently enhance itsoncogenic activity. The goal of this proposal is to understand the mechanisms and consequences of thedestruction of Myc by the Ub-proteasome system.
Four Specific Aims are proposed.
Aim 1 will investigatethe mechanisms through which Myc stability is regulated. Much of this analysis will focus on the identificationand characterization of proteins that interact with a central element within Myc that is important for its post-ubiquitylation destruction.
Aim 2 is focused on understanding how the adenoviral oncoprotein E1A stabilizesMyc, and the contribution of this activity to E1A's oncogenic capabilities.
In Aim 3, the emphasis will shift toanalysis of a highly-conserved, but little-studied, element in Myc that is important for Myc turnover andcontributes to oncogenic transformation by dampening the ability of Myc to induce apoptosis. Finally, in Aim4, the activity of a number of tumor-derived, stable, Myc mutants will be studied in detail to learn themechanisms though which Myc function is perturbed in cancer. These studies make extensive use of cellbased assays, RNAi, microarray experiments, proteomic analyses, as well as cutting-edge mouse models oflymphomagenesis, hepatocellular carcinoma, and breast cancer. Because the Ub-proteasome system isemerging as an attractive target for anti-tumor therapies, understanding how and why Myc is destroyedoffers the potential to reveal new strategies for treating human cancer.
On, Kin Fan; Jaremko, Matt; Stillman, Bruce et al. (2018) A structural view of the initiators for chromosome replication. Curr Opin Struct Biol 53:131-139 |
Knott, Simon R V; Wagenblast, Elvin; Khan, Showkhin et al. (2018) Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554:378-381 |
Shamay, Yosi; Shah, Janki; I??k, Mehtap et al. (2018) Quantitative self-assembly prediction yields targeted nanomedicines. Nat Mater 17:361-368 |
Tramentozzi, Elisa; Ferraro, Paola; Hossain, Manzar et al. (2018) The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592. Cell Cycle 17:1102-1114 |
Arun, Gayatri; Diermeier, Sarah D; Spector, David L (2018) Therapeutic Targeting of Long Non-Coding RNAs in Cancer. Trends Mol Med 24:257-277 |
Tarumoto, Yusuke; Lu, Bin; Somerville, Tim D D et al. (2018) LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. Mol Cell 69:1017-1027.e6 |
Xu, Yali; Milazzo, Joseph P; Somerville, Tim D D et al. (2018) A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia. Cancer Cell 33:13-28.e8 |
Huang, Yu-Han; Klingbeil, Olaf; He, Xue-Yan et al. (2018) POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev 32:915-928 |
Livshits, Geulah; Alonso-Curbelo, Direna; Morris 4th, John P et al. (2018) Arid1a restrains Kras-dependent changes in acinar cell identity. Elife 7: |
Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129 |
Showing the most recent 10 out of 610 publications