TRIM25 has a dual function in the p53/Mdm2 circuit

Abstract

P53 is an important tumor suppressor that, upon activation, induces growth arrest and cell death. Control of p53 is thus of prime importance for proliferating cells, but also for cancer therapy, where p53 activity contributes to the eradication of tumors. Mdm2 functionally inhibits p53 and targets the tumor suppressor protein for degradation. In a genetic screen, we identified TRIM25 as a novel regulator of p53 and Mdm2. TRIM25 increased p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26 S proteasomes. TRIM25 co-precipitated with p53 and Mdm2 and interfered with the association of p300 and Mdm2, a critical step for p53 polyubiquitination. Despite the increase in p53 levels, p53 activity was inhibited in the presence of TRIM25. Downregulation of TRIM25 resulted in an increased acetylation of p53 and p53-dependent cell death in HCT116 cells. Upon genotoxic insults, TRIM25 dampened the p53-dependent DNA damage response. The downregulation of TRIM25 furthermore resulted in massive apoptosis during early embryogenesis of medaka, which was rescued by the concomitant downregulation of p53, demonstrating the functional relevance of the regulation of p53 by TRIM25 in an organismal context.

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

“…For example, Morris and colleagues showed that liver-specific deletion of p53 results in liver cancer (both HCC and cholangiocarcinomas) in about 41% of mice at 10 months, along with increased transforming growth factor-beta levels [24]. It is noteworthy that the expression levels of p53 are regulated by various E3 ubiquitin ligases, including TRIM proteins, such as TRIM25 and TRIM59 [25,26]. In the present study, we showed that TRIM11 similarly decreased the expression levels of p53 and regulated its downstream molecules in vitro and in vivo.…”

A Single Let-7 MicroRNA Bypasses LIN28-Mediated Repression

“…Let-7 preE serves as a platform to recruit RNA-binding proteins such as LIN28, KHSRP (also known as KSRP), hnRNPA1 and TRIM25, in order to posttranscriptionally regulate let-7 biogenesis(Heo et al, 2008; Michlewski and Caceres, 2010; Newman et al, 2008; Rybak et al, 2008; Trabucchi et al, 2009; Viswanathan et al, 2008; Zhang et al, 2015). LIN28 proteins play pervasive roles during animal development and are often dysregulated in cancer(Ambros and Horvitz, 1984; Moss et al, 1997; Moss and Tang, 2003; Shyh-Chang and Daley, 2013; Thornton and Gregory, 2012).…”

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

“…Indeed, TRIM24 (Allton et al, 2009), TRIM39 (Zhang et al, 2012a,b) and TRIM59 (Zhou et al, 2014) help to degrade p53. In addition, TRIM8, TRIM13, TRIM19, TRIM21 and TRIM25 also affect p53 stability (Bernardi et al, 2004;Joo et al, 2011;Caratozzolo et al, 2012;Reddy et al, 2014;Zhang et al, 2015). TRIM28, TRIM29 and TRIM32 antagonize p53 function (Wang et al, 2005;Yuan et al, 2010;Liu et al, 2014).…”