Department of Cancer Biology
Oregon Health & Science University
Evading cellular programs that limit growth and proliferation is required for both tumor formation and maintenance. The work presented in this dissertation uncovers two novel mechanisms through which USP36, a key nucleolar deubiquitinating enzyme (DUB) implicated in ribosome biogenesis, regulates cell growth and proliferation. First, we show that USP36 is an evolutionarily conserved histone 2b deubiquitinase and that it catalyzes the removal of monoubiquitinated histone 2b (H2bub1). We show that through deubiquitination of this histone mark, USP36 can repress the expression of the cell cycle inhibitor p21. Depletion of endogenous USP36 induced the levels of p21 and markedly suppressed cell proliferation. Second, we report USP36 as a novel DUB regulating the p53-MDM2 signaling pathway. We show that USP36 interacts with, deubiquitinates, and stabilizes both p53 and MDM2. Our results demonstrate that USP36 is a bona fide DUB for both MDM2 and p53 and imply that it may play a critical role in regulating p53 activity in cells. Our current work builds upon USP36’s established role in promoting ribosome biogenesis and cell growth, through stabilization of c-Myc, Nucleophosmin and RNA Polymerase I. Thus, we provide additional rationale for pursuing it as a therapeutic target.
School of Medicine
DeVine, Tiffany, "Novel functions of USP36 : regulation of histone 2B and the P53-MDM2 pathway through deubiquitination" (2015). Scholar Archive. 3728.