All ETDs from UAB

Advisory Committee Chair

Tim M Townes

Advisory Committee Members

Christopher A Klug

Hengbin Wang

Rui Zhao

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Protein arginine methylation is a common type of post-translational modifications. Protein arginine methyltransferase 1 (PRMT1) is the predominant PRMT that is involved in diverse physiological and pathological processes in mammalian cells. Dysregulation of PRMT1 is often positively correlated with cancer development, yet many aspects of PRMT1’s role in cancer, especially in acute megakaryoblastic leukemia (AMKL) remain unclear. We identified two PRMT1-methylated substrates and how they impact normal and abnormal megakaryopoiesis. In this dissertation, we demonstrate that dual-specificity protein phosphatase 4 (DUSP4) and RNA binding motif protein 15 (RBM15), two crucial factors for megakaryocytic (MK) differentiation, are methylated by PRMT1 and methylation leads to protein degradation. DUSP4 promotes MK differentiation during lineage commitment via dephosphorylation of p38 kinase; RBM15 controls the alternative splicing of genes important for MK differentiation, such as RUNX1 and GATA1. PRMT1-induced downregulation of DUSP4 and RBM15 are found in AMKL cell lines. Restoring the protein of DUSP4 or RBM15 can rescue terminal MK differentiation blocked by PRMT1 overexpression. Therefore, PRMT1 regulates MAPK signals and RNA splicing in MK cells via methylation of DUSP4 and RBM15, indicating the integration of arginine methylation into phosphorylation-mediated signal pathways. Furthermore, our lab found a live-cell fluorescent dye that selectively associates with cellular PRMT1 protein and emits fluorescent signals for FACS analysis. Taken together, our work revealed two novel PRMT1-controlled signal pathways that are potential therapeutic targets, as well as a novel flow cytometry-based method to stain PRMT1 in live cells.

Share

COinS