RESEARCH TOPICS

Characterization of the Novel Interaction of NORE1A and β-TrCP.

Ras is the most frequently activated oncogene found in human cancer but its mechanisms of action remain only partially understood.  Ras activates multiple signaling pathways in order to promote transformation, however, Ras can also exhibit a potent ability to induce growth arrest and death.  NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and cell cycle arrest.  Expression of NORE1A is frequently lost in human tumors and its mechanism of action remains unclear.  Here we show that NORE1A forms a direct, Ras regulated complex with β-TrCP, the substrate recognition component of the SCF-β-TrCP ubiquitin ligase complex.  This interaction allows Ras to stimulate the ubiquitin ligase activity of SCF-β-TrCP towards its target β-catenin, resulting in degradation of β-catenin   by the 26S proteasome.  However, the action of Ras/NORE1A/β-TrCP is substrate specific, as IκB, another substrate of SCF-β-TrCP, is not sensitive to NORE1A promoted degradation.   Thus we identify a completely new signaling mechanism for Ras that allows for the specific regulation of SCF-β-TrCP targets.  We show that the NORE1A levels in a cell may dictate the effects of Ras on the Wnt/β-catenin pathway.  Moreover, as NORE1A expression is frequently impaired in tumors, we provide an explanation for the observation that β-TrCP can act as a tumor suppressor or an oncogene in different cell systems.

Thesis Committee

1. Geoffrey J. Clark, PHTX/BMB
2. Barbara J. Clark, BMB
3. Robert Mitchell, BMB
4. Jaydev Dholakia, BMB
5. Thomas Geoghegan, BMB

Publications and Dissertations

1. Schmidt, M.L., H. Donninger, and G.J. Clark,Ras regulates SCF-beta-TrCP activity and specificity via its effector NORE1A. J Biol Chem, 2014.
2. Donninger, H., et al., Cell cycle restriction is more important than apoptosis induction for RASSF1A tumor suppression.J Biol Chem, 2014.
3. Schmidt L, C.G., RASSF5 (Ras association (RalGDS/AF-6) domain family member 5). Atlas Genet Cytogenet Oncol Haematol, 2011.
4. Schaeffer, L.M., M.L. Schmidt, and D.R. Demuth, Induction of Aggregatibacter actinomycetemcomitans leukotoxin expression by IS1301 and orfA.Microbiology, 2008. 154(Pt 2): p. 528-38.

For Recent Publications, check PubMed Author search.

Posters Presented

• The Novel Interaction of NORE1A and β-TrCP Connects Ras to the Wnt Pathway.  M. Lee Schmidt, Howard Donninger, and Geoffrey J. Clark.  James Graham Brown Cancer Center Retreat and Research! Louisville (September 2013).  Louisville, KY

More about M. Lee Schmidt (Ex-President)

Lee attended High School at Floyd Central High School graduating in 1999.  He got a B.S. from the University of Louisville in 2004 in Biology and went on to work professionally.  He started in Oral Biology Research and then transitioned to work for LabCorp in Clinical Microbiology and eventually at the Research and Development Headquarters of the company in Research Triangle Park, NC.  Lee returned to graduate school to pursue a PhD is Biochemistry and Molecular Biology in 2010.  He earned his M.S. in Biochemistry and Molecular Biology in 2013 and has served as President of Students of the Biochemistry and Molecular Biology Department from 2013-2014.

Lee works with Dr. Geoffrey Clark and they focus their research on oncogenic signaling.  Currently, Lee works on a negative Ras effector named NORE1A.  NORE1A is a key tumor suppressor, however, its tumor suppressive mechanism remains largely uncharacterized.  The focus of Lee’s dissertation work is characterizing a novel interaction between NORE1A and β-TrCP and the impact this has on tumor suppression.  Feel free to contact him with any questions at lee.schmidt@louisville.edu.