OHSU

Rosalie C. Sears, Ph.D.

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503 494-6885

Background

Research in the sears lab focuses on cellular signaling pathways that coordinately control cell proliferation and cell fate decisions. These pathways are deregulated in human cancer. Our research centers on the c-Myc oncoprotein, which is overexpressed in the majority of human tumors. We are studying regulatory pathways that control c-Myc protein stability as well as its activity. We have identified a complex signaling pathway that regulates c-Myc turnover via ubiquitin-mediated degradation. This pathway targets two conserved phosphorylation sites in c-Myc, Threonine 58 (T58) and Serine 62 (S62), which have opposing effects on c-Myc stability. Phosphorylation at S62 increases Myc stability while phosphorylation at T58 destabilizes Myc. Phosphorylation at these sites is regulated by Ras-activated signaling pathways, the PP2A phosphatase, the Pin1 prolyl isomerase, and the Axin scaffolding protein, which coordinates these enzymes into a destruction complex for c-Myc. Most of the proteins on this pathway can be deregulated in human cancer, and we have shown that c-Myc is aberrantly stabilized in many tested human cancer cell lines and primary patient samples and this is associated with elevated S62 phosphorylation and reduced T58 phosphorylation. Moreover, recent evidence from our lab and others indicates that these phosphorylation sites also control c-Myc’s apoptotic and tumorigenic potential, thus coupling c-Myc stability to its function such that stabilized Myc with elevated P-S62 has increased oncogenic activity. This paradigm shift in our understanding of c-Myc provides a pathway for therapeutic intervention targeting post-translational regulation of c-Myc in human cancer.


Selected Publications

"Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia," Clinical Cancer Research (Vol: 20, Issue: 8, Page 2092-2103) - 2014

"Diminished WNT → β-catenin → c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors," Genes and Development (Vol: 28, Issue: 6, Page 561-575) - 2014

"MYC degradation," Cold Spring Harbor Perspectives in Medicine (Vol: 4, Issue: 3, ) - 2014

"Detection of c-Myc protein-protein interactions and phosphorylation status by immunoprecipitation," Methods in Molecular Biology (Vol: 1012, Page 65-76) - 2013

"N terminus of ASPP2 binds to Ras and enhances Ras/Raf/MEK/ERK activation to promote oncogene-induced senescence," Proceedings of the National Academy of Sciences of the United States of America (Vol: 110, Issue: 1, Page 312-317) - 2013

 

OHSU Knight Cancer Institute

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  Email Rosalie Sears

503 494-8311

Memberships & Associations

American Association for Cancer Research