Myc proteins are essential for normal cellular function and embryonic development. However, when its normal regulation is compromised, Myc acts as a major contributor to the initiation and progression of a wide range of human cancers. Myc has been long known to be a transcription factor that heterodimerizes with the Max protein. The Myc-Max dimer binds DNA and regulates expression of thousands of genes involved in cell growth and proliferation. The long-term objectives of this grant application, as embodied in our three Specific Aims, are to elucidate two previously unexplored tumor-specific pathways through which Myc drives neoplasia and to devise an approach to specifically inhibit Myc activity.
In Aim 1 we extend our recent discovery of a transcriptionally inactive form of Myc which promotes survival and motility of cancer cells. We have shown that Myc protein is proteolytically cleaved to generate a cytoplasmic, transcriptionally inactive, N-terminal segment of Myc, denoted as Myc-nick. Myc-nick is produced in response to growth arrest or stress, and is present in a wide range of human tumors. Through its ability to interact with acetyltransferases, Myc-nick acetylates cytoplasmic proteins, alters cell morphology, promotes survival and stimulates filopodia formation and cell motility. We propose experiments, using tumor models in Zebrafish and mice, to determine the involvement of Myc-nick in tumor progression and metastasis. In addition, we will employ proteomics to identify Myc-nick interacting proteins and the molecular basis for Myc- nick's functions.
Aim 2 is focused on a gain of oncogenic function caused by a point mutation in Myc. This coding region mutation (Myc-T58A), which occurs in the conserved Myc phospho-degron (Myc Box I), accelerates oncogenicity of overexpressed Myc. To separate the effects of the T58A mutation from the effects of Myc overexpression, we generated mice containing T58A in the endogenous myc locus. In these mice Myc- T58A is normally regulated and there is no overt increase in tissue growth or proliferation. Yet c-myc-T58A mice display increased hematopoietic progenitor cell self-renewal and exhibit a long-latency tumor-prone phenotype. We surmise that the Myc-T58A mutation alters a protein interaction with Myc Box I and influences activation of a subpopulation of Myc target genes. We plan to identify the basis for the T58A phenotypes using proteomic and genomic analyses.
In Aim 3 we propose to generate highly specific peptide-based inhibitors of Myc-Max dimerization using binding selection of ~104 Max variants coupled with high-throughput sequencing. Peptides that inhibit Max dimerization with Myc, but not with Mxd repressors, will be examined for their ability to inhibit growth of Myc-driven tumors. This general approach can be applied to other critical protein interactions. We anticipate that the studies proposed in this application will lead to new insights into Myc's activities in cancer and to novel approaches aimed at inhibiting the function of this critical oncogene.

Public Health Relevance

The Myc protein is an essential regulator of growth in all normal cells, but in many cancers Myc is unregulated and supports high rates of growth needed for tumor progression. In this proposal we will determine what events contribute to activation of Myc in tumors and devise an approach to inhibit Myc function. This research is relevant to public health because it will ultimately lead a better understanding of the causes for cancer and lead to new approaches to cancer therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Hiler, Daniel J; Barabas, Marie E; Griffiths, Lyra M et al. (2016) Reprogramming of mouse retinal neurons and standardized quantification of their differentiation in 3D retinal cultures. Nat Protoc 11:1955-1976
Kim, Dong-Wook; Wu, Nan; Kim, Young-Chul et al. (2016) Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer. Genes Dev 30:1289-99
Anderson, Sarah; Poudel, Kumud Raj; Roh-Johnson, Minna et al. (2016) MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation. Proc Natl Acad Sci U S A 113:E5481-90
Diolaiti, Daniel; McFerrin, Lisa; Carroll, Patrick A et al. (2015) Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis. Biochim Biophys Acta 1849:484-500
Hiler, Daniel; Chen, Xiang; Hazen, Jennifer et al. (2015) Quantification of Retinogenesis in 3D Cultures Reveals Epigenetic Memory and Higher Efficiency in iPSCs Derived from Rod Photoreceptors. Cell Stem Cell 17:101-15
Conacci-Sorrell, Maralice; McFerrin, Lisa; Eisenman, Robert N (2014) An overview of MYC and its interactome. Cold Spring Harb Perspect Med 4:a014357
Conacci-Sorrell, Maralice; Ngouenet, Celine; Anderson, Sarah et al. (2014) Stress-induced cleavage of Myc promotes cancer cell survival. Genes Dev 28:689-707
Sanchez-Arévalo Lobo, V J; Doni, M; Verrecchia, A et al. (2013) Dual regulation of Myc by Abl. Oncogene 32:5261-71
Haskins, William E; Zablotsky, Bethany L; Foret, Michael R et al. (2013) Molecular Characteristics in MRI-Classified Group 1 Glioblastoma Multiforme. Front Oncol 3:182
Pshenichnaya, Irina; Schouwey, Karine; Armaro, Marzia et al. (2012) Constitutive gray hair in mice induced by melanocyte-specific deletion of c-Myc. Pigment Cell Melanoma Res 25:312-25

Showing the most recent 10 out of 62 publications