Ubiquitylation of p53 by the APC/C inhibitor Trim39.
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Tripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.
SubjectAmino Acid Motifs
Cyclin-Dependent Kinase Inhibitor p21
RNA, Small Interfering
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligase Complexes
Published Version (Please cite this version)10.1073/pnas.1212047110
Publication InfoZhang, L; Huang, NJ; Chen, C; Tang, W; & Kornbluth, S (2012). Ubiquitylation of p53 by the APC/C inhibitor Trim39. Proc Natl Acad Sci U S A, 109(51). pp. 20931-20936. 10.1073/pnas.1212047110. Retrieved from http://hdl.handle.net/10161/8389.
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Jo Rae Wright University Professor
Our lab studies the regulation of complex cellular processes, including cell cycle progression and programmed cell death (apoptosis). These tightly orchestrated processes are critical for appropriate cell proliferation and cell death, and when they go awry can result in cancer and degenerative disorders. Within these larger fields, we have focused on understanding the cellular mechanisms that prevent the onset of mitosis prior to the completion of DNA replication, the process