Focusing on post-translational protein regulation for cancer intervention
The c-Myc oncogene, regularly highly-expressed in most human tumors, has long been of interest to researchers seeking therapeutic targets for cancer treatments. Rosalie Sears, PhD, Associate Professor in the Department of Molecular and Medical Genetics, is pursuing a road-less- traveled in her research on this oncogene by focusing her attention on the post-translational regulation of the c-Myc oncoprotein.
Dr. Sears is working on a hypothesis that the aberrant stabilization of this protein - due to altered post-translational regulation at two phosphorylation sites - is important to its elevated levels in human cancers. Understanding the regulatory mechanism of these elevated levels may offer new promising opportunities for therapeutic intervention.
“This is a new way of looking at c-Myc that could help to develop viable therapeutic options for targeting this key oncoprotein,” said Dr. Sears.
c-Myc in its normal state has a relatively short half-life of around 20 minutes. In a healthy cell, it is typically expressed at continuously low levels. The one period where this is not the case occurs in response to mitogen stimulation when a cell is pushed from an arrested state to enter the cell cycle and proceed to DNA synthesis. Elevated c-Myc expression is necessary to drive this transition. Once DNA synthesis has been achieved, c-Myc expression returns to its typically low levels as the cell continues to cycle.
This high point of c-Myc expression is the focus of Dr. Sears’ research. She believes that cancer commandeers the mechanism promoting c-Myc’s high expression and that during this stage c-Myc is not disposed to cause cell death and is highly potent. Two pathways regulate the phosphorylation and stability of c-Myc at this critical point, and abnormal activity of either pathway can slow the degradation of the protein, causing it to be expressed at higher levels for longer periods and triggering aberrant cell proliferation. Simultaneously, Dr. Sears’ research has advanced understanding of the tumor suppressor activity of the PP2A-B56a phosphatase that facilitates c-Myc degradation, and of the scaffold-like role of the protein Axin1, which acts a tumor-suppressor and docking station that supports the kinases and phosphatase that regulate c-Myc phosphorylation and degradation.
Dr. Sears is using transgenic knock-in mice that express c-Myc with altered phosphorylation and stability in her research. These mouse models of tumors and blood-borne cancers gives Dr. Sears greater specificity to aid in developing therapeutic treatments.
“This work is really exciting because if we could re-establish the normal phosphorylation and rapid degradation of c-Myc we could both lower c-Myc levels and potentially turn back on its ability to induce cell death, resulting in potent tumor regression.”
Dr. Sears’ work has been supported by grants from the Susan G. Komen Breast Cancer Foundation, the Department of Defense, the National Cancer Institute and the Leukemia & Lymphoma Society. A graduate of Reed College, Dr. Sears obtained her PhD in Cell Biology from Vanderbilt University Medical Center, and conducted post-doctoral work at Duke University Medical Center.
