Human tripartite motif protein 52 is required for cell context-dependent proliferation

Abstract

Tripartite motif (TRIM) proteins have been shown to play important roles in cancer development and progression by modulating cell proliferation or resistance from cell death during non-homeostatic stress conditions found in tumor micro-environments. In this study, we set out to investigate the importance for cellular fitness of the virtually uncharacterized family member TRIM52.The human TRIM52 gene has arisen recently in evolution, making it unlikely that TRIM52 is required for basic cellular functions in normal cells. However, a recent genome-wide ablation screening study has suggested that TRIM52 may be essential for optimal proliferation or survival in certain genetic cancer backgrounds. Identifying genes which fit this concept of genetic context-dependent fitness in cancer cells is of interest as they are promising targets for tumor-specific therapy.We report here that TRIM52 ablation significantly diminished the proliferation of specific glioblastoma cell lines in cell culture and mouse xenografts by compromising their cell cycle progression in a p53-dependent manner. Together, our findings point to a non-redundant TRIM52 function that is required for optimal proliferation.

A repetitive acidic region contributes to the extremely rapid degradation of the cell-context essential protein TRIM52

“…Several independent studies have recently identified TRIM52 as an essential factor in various cancer cell lines, whose expression is deregulated in primary cancer samples 8–10 . In this study we characterized how TRIM52 itself is regulated.…”

“…Subsequently, similar observations have been reported by independent groups, positioning TRIM52 as an important regulator of cell proliferation 9,10 . Epistasis experiments from our group, as well as independent studies indicate that a TRIM52 -ablation phenotype requires a wild-type TP53 allele (encoding the p53 protein) 8,9 . TRIM52 has been reported to ubiquitinate the p53-inhibitor PPM1A, thereby suppressing p53-dependent cell-cycle arrest 9 .…”

“…Unexpectedly, we recently found that TRIM52 ablation is detrimental for cell cycle progression and thus proliferation in certain human cancer cell lines in cell culture and mouse xenograft models, without affecting cell viability 8 . Subsequently, similar observations have been reported by independent groups, positioning TRIM52 as an important regulator of cell proliferation 9,10 .…”

E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

“…A common effect of most TRIM proteins, when silenced or knocked-down, is the increase of the percentage of cells in G0/G1 and the reduction of the fraction of cells in S or G2-M phases. Specifically, TRIM8, TRIM14, TRIM27, TRIM28, TRIM29, TRIM52, TRIM59, TRIM66, and TRIM68 led to cell cycle arrest when depleted or silenced [24,25,26,27,28,29,30,31,32,33,34,35].…”

Tripartite Motif Containing 52 Positively Regulates NF-κB Signaling by Promoting IκBα Ubiquitination in Lipopolysaccharide-Treated Microglial Cell Activation

“…TRIM52, a TRIM-protein family member, plays a role in autophagy, innate immunity, and carcinogenesis [ 15 ]. TRIM52 was found to be crucial for cell context-dependent proliferation in a p53-dependent manner [ 16 ]. In addition, it is a positive regulator of NF-κB signaling and plays an oncogenic role in tumorigenesis [ 17 , 18 ], including blocking tumor growth, inhibiting cell proliferation, and promoting cell apoptosis in tumors.…”