Regulation of cell growth and proliferation by Myc

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): 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.