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TRIPARTITE MOTIF-CONTAINING PROTEIN 25; TRIM25

TRIPARTITE MOTIF-CONTAINING PROTEIN 25; TRIM25

Alternative titles; symbolsZINC FINGER PROTEIN 147; ZNF147ESTROGEN-RESPONSIVE FINGER PROTEIN; EFPHGNC Approved Gene Symbol: TRIM25Cytogenetic location: 17q22 ...

Alternative titles; symbols

  • ZINC FINGER PROTEIN 147; ZNF147
  • ESTROGEN-RESPONSIVE FINGER PROTEIN; EFP

HGNC Approved Gene Symbol: TRIM25

Cytogenetic location: 17q22 Genomic coordinates (GRCh38): 17:56,887,908-56,914,048 (from NCBI)

▼ Cloning and Expression
The human estrogen-responsive finger protein, a member of the RING finger protein family, was isolated by Inoue et al. (1993) from a human placenta cDNA library using an estrogen receptor-binding fragment containing an estrogen-responsive element. Since this estrogen-responsive finger protein is induced by estrogen via an estrogen-responsive element (ERE) in the 3-prime untranslated region of the gene, it is an attractive candidate for the correlation between estradiol levels and breast/ovarian cancer risk.

▼ Mapping
By fluorescence in situ hybridization, Inoue et al. (1995) demonstrated that the human EFP gene, also called ZNF147, is located on 17q23.1 and that mouse Efp is located at 11C. Law et al. (1995) demonstrated that the ZNF147 gene is located within a YAC contig containing the myeloperoxidase (MPO; 606989) gene. Approximately 300 kb separate the 2 loci. This result was confirmed by fluorescence in situ hybridization, which again showed that the EFP gene is located at 17q23.1 and refined the assignment of the location of MPO to the same site. At the same time, they mapped the homologous gene in the mouse to chromosome 11 near the Mpo gene.

▼ Gene Function
Urano et al. (2002) demonstrated that EFP is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3-sigma (601290), a negative cell cycle regulator that causes G2 arrest. Urano et al. (2002) demonstrated that tumor growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generated tumors in the absence of estrogen. Loss of Efp function in mouse embryonic fibroblasts resulted in an accumulation of 14-3-3-sigma, which was responsible for reduced cell growth. Urano et al. (2002) concluded that their data provide an insight into the cell cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3-sigma as a target for proteolysis by EFP, leading to cell proliferation.

Gack et al. (2007) reported that the N-terminal caspase recruitment domains (CARDs) of RIGI (609631) undergo robust ubiquitination induced by TRIM25 in mammalian cells. The C-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIGI; this interaction effectively delivers the lys63-linked ubiquitin moiety to the N-terminal CARDs of RIGI, resulting in a marked increase in RIGI downstream signaling activity. The lys172 residue of RIGI is critical for efficient TRIM25-mediated ubiquitination and for MAVS (609676) binding, as well as the ability of RIGI to induce antiviral signal transduction. Gene targeting demonstrated that TRIM25 is essential not only for RIGI ubiquitination but also for RIGI-mediated interferon-beta (see 147640) production and antiviral activity in response to RNA virus infection. Thus, Gack et al. (2007) demonstrated that TRIM25 E3 ubiquitin ligase induces the lys63-linked ubiquitination of RIGI, which is crucial for the cytosolic RIGI signaling pathway to elicit host antiviral innate immunity.

Dengue virus (see 614371) may become more virulent or show greater outbreak potential in a population exposed to new viral strains. Manokaran et al. (2015) identified a determinant of fitness in a new clade (PR-2B) of Dengue virus serotype-2 (DENV-2) that became dominant during a 1994 epidemic in Puerto Rico and replaced an endemic clade (PR-1) of DENV-2. PR-2B DENV-2 showed increased levels of subgenomic flavivirus RNA (sfRNA) compared with genomic RNA during replication. PR-2B sfRNA exhibited sequence-dependent binding to and prevention of TRIM25 deubiquitylation, which is required for sustained and amplified RIGI-induced type I interferon (see 147640) expression. Manokaran et al. (2015) concluded that a distinctive viral RNA-host protein interaction leads to evasion of the innate immune response, resulting in increased epidemiologic fitness of the new viral strain.

▼ Animal Model
Orimo et al. (1999) generated mice carrying a loss-of-function mutation in Efp by gene-targeted mutagenesis. Although Efp -/- mice were viable and fertile in both sexes, the uterus, which expressed abundant estrogen receptor-alpha (133430), exhibited significant underdevelopment. When the ovariectomized mutants were subject to 17-beta-estradiol treatment, they showed remarkably attenuated responses to estrogen, as exemplified by decreased interstitial water imbibition and retarded endometrial cell increase, attributable at least in part to the lower ratio of G1 to S-phase progression in epithelial cells. Orimo et al. (1999) concluded that EFP is essential for the normal estrogen-induced cell proliferation and uterine swelling and is one of the direct targets of estrogen receptor-alpha.

Tags: 17q22