The myc family of proto-oncogenes is linked with a remarkable number of human cancers and with up to 15% of all human cancer deaths, however the etiology of these cancers remains largely unknown. The general goal of this proposal is to elucidate the mechanism by which deregulation of myc genes leads to tumorigenesis. More specifically, the focus is on analyzing nervous system tumors associated with myc genes, such as medulloblastoma, retinoblastoma, and neuroblastoma. These tumors are devastating cancers that most often occur in children and the current treatments are themselves associated with a high degree of morbidity, providing a particularly compelling impetus to better understand and more effectively treat these cancers.
In Aim 1, the normal functions of myc genes in the nervous system will be analyzed using mouse knockouts, based on the premise that understanding the normal functions of proto-oncogenes often provides critical clues as to how they cause cancer when in excess. The myc knockouts are conditionally targeted to neural progenitor cells, the cells of origin for many nervous system tumors.
In Aim 2, using myc transgenic mice, where myc is overexpressed in neural progenitors as in tumors, the goal is to study a nervous system tumor model. One area of particular interest in both of these aims is the cerebellum, where N-myc is both critical for normal development, probably as a Sonic Hedgehog effector, and where it is implicated in the genesis of medulloblastoma.
In Aim 3, the link between myc and global chromatin histone modifications will be addressed. Excess myc drives high levels of histone acetylation suggesting that global changes in chromatin modification could may be linked to Myc-induced tumorigenesis. Together these aims will cooperatively address the research goals of defining how myc genes function in neurogenesis and induce neural cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01CA114400-01
Application #
6912993
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2005-07-01
Project End
2006-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$100,569
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Laskowski, Agnieszka I; Knoepfler, Paul S (2013) Myc binds the pluripotency factor Utf1 through the basic-helix-loop-helix leucine zipper domain. Biochem Biophys Res Commun 435:551-6
Martínez-Cerdeño, Verónica; Lemen, Jessica M; Chan, Vanessa et al. (2012) N-Myc and GCN5 regulate significantly overlapping transcriptional programs in neural stem cells. PLoS One 7:e39456
Varlakhanova, Natalia V; Cotterman, Rebecca F; deVries, Wilhelmine N et al. (2010) myc maintains embryonic stem cell pluripotency and self-renewal. Differentiation 80:9-19
Wey, Alice; Knoepfler, Paul S (2010) c-myc and N-myc promote active stem cell metabolism and cycling as architects of the developing brain. Oncotarget 1:120-30
Cotterman, Rebecca; Knoepfler, Paul S (2009) N-Myc regulates expression of pluripotency genes in neuroblastoma including lif, klf2, klf4, and lin28b. PLoS One 4:e5799
Cotterman, Rebecca; Jin, Victor X; Krig, Sheryl R et al. (2008) N-Myc regulates a widespread euchromatic program in the human genome partially independent of its role as a classical transcription factor. Cancer Res 68:9654-62
Knoepfler, Paul S (2007) Myc goes global: new tricks for an old oncogene. Cancer Res 67:5061-3
Knoepfler, Paul S; Kenney, Anna Marie (2006) Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes. Cell Cycle 5:47-52
Knoepfler, Paul S; Zhang, Xiao-yong; Cheng, Pei Feng et al. (2006) Myc influences global chromatin structure. EMBO J 25:2723-34

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