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Characterization of the oncogenic activity of the novel TRIM59 gene in mouse cancer models
Fatma Valiyeva1, Fei Jiang, Ahmed Elmaadawi
1Lawson Health Research Institute, University of Western Ontario, 375 South Street, London, ON, N6A 4G5, Canada.
Abstract:
A novel TRIM family member, TRIM59 gene was characterized to be upregulated in SV40 Tag oncogene-directed transgenic and knockout mouse prostate cancer models as a signaling pathway effector. We identified two phosphorylated forms of TRIM59 (p53 and p55) and characterized them using purified TRIM59 proteins from mouse prostate cancer models at different stages with wild-type mice and NIH3T3 cells as controls. p53/p55-TRIM59 proteins possibly represent Ser/Thr and Tyr phosphorylation modifications, respectively. Quantitative measurements by ELISA showed that the p-Ser/Thr TRIM59 correlated with tumorigenesis, whereas the p-Tyr-TRIM59 protein correlated with advanced cancer of the prostate (CaP). The function of TRIM59 was elucidated using short hairpin RNA (shRNA)-mediated knockdown of the gene in human CaP cells, which caused S-phase cell-cycle arrest and cell growth retardation. A hit-and-run effect of TRIM59 shRNA knockdown was observed 24 hours posttransfection. Differential cDNA microarrray analysis was conducted, which showed that the initial and rapid knockdown occurred early in the Ras signaling pathway. To confirm the proto-oncogenic function of TRIM59 in the Ras signaling pathway, we generated a transgenic mouse model using a prostate tissue-specific gene (PSP94) to direct the upregulation of the TRIM59 gene. Restricted TRIM59 gene upregulation in the prostate revealed the full potential for inducing tumorigenesis, similar to the expression of SV40 Tag, and coincided with the upregulation of genes specific to the Ras signaling pathway and bridging genes for SV40 Tag-mediated oncogenesis. The finding of a possible novel oncogene in animal models will implicate a novel strategy for diagnosis, prognosis, and therapy for cancer.
Insights
The TRIM59 gene acts as a novel oncogene in prostate cancer, with its phosphorylation levels correlating to tumor progression. Knockdown studies revealed its role in cell cycle regulation and the Ras signaling pathway, suggesting potential diagnostic and therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The TRIM59 gene, a novel member of the TRIM family, is implicated in cancer development.
- Its role as a signaling pathway effector in prostate cancer models is under investigation.
Purpose of the Study:
- To characterize the novel TRIM59 gene and its phosphorylated forms in prostate cancer.
- To elucidate the function of TRIM59 in cancer progression and the Ras signaling pathway.
Main Methods:
- Utilized SV40 Tag oncogene-directed transgenic and knockout mouse prostate cancer models.
- Identified and characterized phosphorylated TRIM59 forms (p53, p55) using ELISA.
- Performed short hairpin RNA (shRNA)-mediated knockdown in human prostate cancer cells.
- Conducted differential cDNA microarray analysis and generated a prostate-specific TRIM59 transgenic mouse model.
Main Results:
- TRIM59 is upregulated in prostate cancer models and exists in two phosphorylated forms, p53 and p55, potentially representing Ser/Thr and Tyr modifications.
- Phospho-Ser/Thr TRIM59 correlates with tumorigenesis, while phospho-Tyr TRIM59 correlates with advanced prostate cancer.
- TRIM59 knockdown induces S-phase cell-cycle arrest and growth retardation, impacting the Ras signaling pathway.
- Prostate-specific TRIM59 upregulation induces tumorigenesis, mirroring SV40 Tag effects and activating Ras signaling.
Conclusions:
- TRIM59 functions as a novel proto-oncogene in prostate cancer, particularly through its influence on the Ras signaling pathway.
- The phosphorylation status of TRIM59 serves as a potential biomarker for cancer progression.
- TRIM59 represents a potential novel target for cancer diagnosis, prognosis, and therapy.
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