Abstract 14019: Nucleostemin is Induced by Pim-1-Mediated c-Myc Stabilization That Enhances Regenerative Potential and Survival of Cardiac Progenitor Cells
Myocardial regeneration and repair in response to injury is governed by cell survival and proliferation. Signaling molecules and pathways mediating enhanced survival and proliferation are of significant interest to understand stem cells mediated myocardial repair. Proliferation and survival in cardiac progenitor cells (CPCs) and cardiac myocytes are mediated by Pim-1, a serine threonine kinase, and nucleostemin (NS), a nucleolar stress sensor protein. This study delineates signaling mechanisms underlying Pim-1-mediated signaling in CPCs and demonstrates the transcription factor c-Myc is a critical intermediate for regulation of NS. c-Myc and NS were increased in CPCs overexpressing Pim-1 (CPCeP) in vitro for both mRNA and protein expression levels. In contrast, knockdown of Pim-1 using si-RNA decreased c-Myc and NS protein expression (-66% and -48% respectively, p<0.01), similar to effects mediated by a Pim-1 kinase inhibitor (quercetagetin) that also significantly reduced c-Myc and NS expression (-78% and -63% respectively; p<0.01) indicating that Pim-1 regulates both c-Myc and NS. Lentiviral mediated over-expression of c-Myc significantly upregulated NS (3.45 fold, p<0.05), whereas pharmacological inhibition using c-Myc inhibitor 10058-F4 decreased NS expression in both CPC and CPCeP (-66%, -32.2%, p<0.05). Similarly, transgenic mice engineered with cardiac-specific Pim-1 overexpression exhibit increased c-Myc and NS levels (1.32 and 1.89 fold respectively, p<0.05), whereas Pim-1 knockout mice decreased expression for both molecules (p<0.05). Thus, c-Myc is required for the regulation of NS and, in the absence of c-Myc, Pim-1 cannot upregulate NS expression. These findings have important implications for the molecular regulation of survival and proliferation and provide a mechanistic explanation for beneficial effects of Pim-1 expression in CPC and cardiac myocytes.
- © 2011 by American Heart Association, Inc.