The proteins encoded by the myc proto-oncogene family normally function as components of a transcriptional regulatory network which mediates cell growth, proliferation, differentiation, and death in response to diverse extracellular signals. All three Myc family genes (c-, N-, and L-myc) are widely expressed during mammalian development. However deregulated over-expression of mycfamily genes is closely tied to the etiology of many different types of cancers. This application is directed towards linking Myc's biological functions during development with Myc's ability to induce transcriptionally-related modifications of chromatin. In the first Aim, the role of N-myc will be studied in the context of the developing mouse nervous system. Using targeted gene deletions, we will define a """"""""Myc pathway"""""""" by delineating the role of N-myc as an effector of cytokine signalling and by determining the importance of a subset of N-myc transcriptional target genes. N-myc has been implicated in tumors of the nervous system and we will use a mouse tumor model involving a constitutively activated Sonic Hedgehog receptor to determine the effects of N-myc deletion and over-expression in the progression of medulloblastoma.
In Aim 2 we extend our studies of Myc function by examining the consequences of deleting N-myc both earlier in development and in a more restricted region of the brain. In addition, we will use targeted deletions of c-myc and L-myc and determine the extent to which the differences in regulation and activites among Myc family members play a role in organogenesis.
In Aim 3 we employ our myc gene deletions to explore the hypothesis that Myc proteins function to regulate the accessibility of large chromatin domains. This model derives from the observations that Myc genomic binding is widespread and that changes in Myc protein levels correlate with changes in both histone modifications and nuclear structure. We will delineate the nature and extent of chromatin modification in response to Myc and determine its consequences by employing cytological and biochemical approaches. Moreover, we will explore the mechanism which underlies Myc's ability to cause global alterations in chromatin.
| 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 |
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