Myc is an oncoprotein transcription factor that features prominently in a variety of human cancers. Indeed, it is estimated that approximately one-third of all cancer deaths in the United States involve inappropriate Myc expression or activity. Cells have evolved a number of mechanisms to restrict Myc expression in normal cells, one of which is ubiquitin (Ub)-mediated proteolysis. The importance of Myc destruction is evidenced by the fact that cancer-associated mutations within Myc block its destruction and potently enhance its oncogenic activity. The goal of this proposal is to understand the mechanisms and consequences of the destruction of Myc by the Ub-proteasome system.
Four Specific Aims are proposed.
Aim 1 will investigate the mechanisms through which Myc stability is regulated. Much of this analysis will focus on the identification and 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 stabilizes Myc, and the contribution of this activity to E1A's oncogenic capabilities.
In Aim 3, the emphasis will shift to analysis of a highly-conserved, but little-studied, element in Myc that is important for Myc turnover and contributes to oncogenic transformation by dampening the ability of Myc to induce apoptosis. Finally, in Aim 4, the activity of a number of tumor-derived, stable, Myc mutants will be studied in detail to learn the mechanisms though which Myc function is perturbed in cancer. These studies make extensive use of cell based assays, RNAi, microarray experiments, proteomic analyses, as well as cutting-edge mouse models of lymphomagenesis, hepatocellular carcinoma, and breast cancer. Because the Ub-proteasome system is emerging as an attractive target for anti-tumor therapies, understanding how and why Myc is destroyed offers the potential to reveal new strategies for treating human cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1)
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Cold Spring Harbor Laboratory
Cold Spring Harbor
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Li, Meng Amy; Amaral, Paulo P; Cheung, Priscilla et al. (2017) A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation. Elife 6:
Diermeier, Sarah D; Spector, David L (2017) Antisense Oligonucleotide-mediated Knockdown in Mammary Tumor Organoids. Bio Protoc 7:
Pelossof, Raphael; Fairchild, Lauren; Huang, Chun-Hao et al. (2017) Prediction of potent shRNAs with a sequential classification algorithm. Nat Biotechnol 35:350-353
Roe, Jae-Seok; Hwang, Chang-Il; Somerville, Tim D D et al. (2017) Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell 170:875-888.e20
Zhang, Bin; Mao, Yuntao S; Diermeier, Sarah D et al. (2017) Identification and Characterization of a Class of MALAT1-like Genomic Loci. Cell Rep 19:1723-1738
Mu, Ping; Zhang, Zeda; Benelli, Matteo et al. (2017) SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355:84-88
Anczuków, Olga; Krainer, Adrian R (2016) Splicing-factor alterations in cancers. RNA 22:1285-301
Baker, Leena; BeGora, Michael; Au Yeung, Faith et al. (2016) Scribble is required for pregnancy-induced alveologenesis in the adult mammary gland. J Cell Sci 129:2307-15
Tasdemir, Nilgun; Banito, Ana; Roe, Jae-Seok et al. (2016) BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. Cancer Discov 6:612-29
Hossain, Manzar; Stillman, Bruce (2016) Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. Elife 5:

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