Mentor:  Miles Pufall, PhD

Year Entered Into Program:  2017

Graduate Program: Biochemistry

Research Description

Elucidating the mechanism of how phosphorylation of GR by Erk2 Attenuates function

Glucocorticoids (GCs), are among the most widely prescribed drugs and are used to effectively treat a variety of disorders from asthma to blood cancers but have limited use due to severe side effects. Recently, we have explored limiting side effects by potentiating GC activity in the tissue of interest. Specifically, we are working on understanding how GCs work to kill leukemia cells in B-cell acute lymphoblastic leukemia (B-ALL) patients. Understanding how this works has the potential to help create more efficient drugs and therapies. Recently in the lab we identified a set if proteins in the RAS/MAPK pathway that when knocked down sensitize cells to dexamethasone (a GC). This sensitizing happens by affecting the glucocorticoid receptor (GR), a GC-activated transcription factor. Inhibition of the lymphoid-restricted PI3Kδ reduces phosphorylation of GR and results in enhanced GR function.  We also showed that inhibition of Erk2, the terminal kinase in the RAS/MAPK pathway, also enhanced GR function, suggesting that it is the kinase that modifies GR.  The goal of this project is to understand how phosphorylation of GR by Erk2 inhibits its function. I will test how phosphorylation affects GR DNA binding specificity, structure, transcriptional activity and co-factor recruitment to determine how GR activity is being attenuated by phosphorylation.

Awards

• Fellowship appointment on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2018-2020

Publications

1. Fowler, C.A., Nunez Hernandez, M.F., O’Donnell, S.E., Yu, L., Shea, M.A.:  Backbone and side-chain resonance assignments of (Ca²⁺) _4-calmodulin bound to beta calcineurin A CaMBD peptide. Biomolecular NMR Assignments. 11(2):275-280, 2017.  PMCID: PMC5693717