Isg15 controls p53 stability and functions

Abstract

Degradation of p53 is a cornerstone in the control of its functions as a tumor suppressor. This process is attributed to ubiquitin-dependent modification of p53. In addition to polyubiquitination, we found that p53 is targeted for degradation through ISGylation. Isg15, a ubiquitin-like protein, covalently modifies p53 at 2 sites in the N and C terminus, and ISGylated p53 can be degraded by the 20S proteasome. ISGylation primarily targets a misfolded, dominant-negative p53, and Isg15 deletion in normal cells results in suppression of p53 activity and functions. We propose that Isg15-dependent degradation of p53 represents an alternative mechanism of controlling p53 protein levels, and, thus, it is an attractive pathway for drug discovery.

Oncogene-mediated regulation of p53 ISGylation and functions

“…The exact role of Isg15 in oncogene-mediated transformation however is still unclear. Therefore, we explored the possibility that Isg15 in cancer cells acts through regulation of p53 as we previously found that Isg15 can efficiently target p53 for degradation [1]. We first tested whether different oncogenes can promote p53 ISGylation.…”

“…Controlling the stability of the p53 tumor suppressor through polyubiquitination and subsequent degradation by the 26S proteasome is central to the regulation of p53 functions. We recently found that in addition to degradation of p53 through the ubiquitin-26S proteasomes-dependent system, it can be modified by Isg15 creating a degradation signal for the 20S proteasomes [1]. This degradation pathway in normal cells, when the Isg15 system is relatively inefficient, appeared to be targeting primarily misfolded, dominant-negative p53.…”

“…This degradation pathway in normal cells, when the Isg15 system is relatively inefficient, appeared to be targeting primarily misfolded, dominant-negative p53. As a consequence, deletion of Isg15 resulted in accumulation of misfolded p53 reducing the overall p53 activity in primary cells including fibroblasts, neural stem/progenitor cells and thymocytes [1]. …”

“…We further found that p53 Tyr 126 and Tyr220 were critically involved in Src-dependent p53 ISGylation through regulation of p53 binding with its E3 ligase, Herc5. Deletion of Isg15 in cancer cells increased both misfolded and native p53, which was in contrast to accumulation of only misfolded form in normal cells [1]. This in turn resulted in upregulation of p53 activity in transformed cells and suppression of tumorigenesis in mice.…”

NGX6a Is Degraded through a Proteasome-dependent Pathway without Ubiquitination Mediated by Ezrin, a Cytoskeleton-Membrane Linker

“…Current evidence suggests that some target proteins also can be bound by other ubiquitin-like proteins. The ubiquitin-like protein family contains small ubiquitin-like modifier (SUMO) proteins (26), NEDD8 (neural precursor cell-expressed developmentally down-regulated protein 8) (27), and ISG15 (interferon-stimulated 15-kDa protein) (28). Ubiquitin is the predominant regulator for the degradation of a wide range of target proteins, whereas SUMO, NEDD8, and ISG15 modify a limited set of substrates to regulate various other biological processes.…”