E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

Ding

et al. 2020

Preprint

Abstract Background Emerging evidence shows that the deregulation of tripartite motif (TRIM) family proteins have various functions in cellular processes and play important role in innate immunity, nervous system diseases, protein quality control and carcinogenesis. However, the precise biological function and molecular mechanism of TRIM family proteins in ovarian cancer chemo-resistance remain unclear. Methods The protein and mRNA expression of TRIM37 in ovarian cancer cell lines and patient tissues were determined using Real-time PCR and Western blot and IHC respectively. Functional assays, such as MTT, FACS, and Tunel assay used to determine the oncogenic role of TRIM37 in human ovarian cancer progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of TRIM37 promotes chemoresistance in ovarian cancer cells. Results Herein, we found that the protein and mRNA expression of TRIM37 were markedly overexpressed in ovarian cancer tissues which shown partially responded to cisplatin chemotherapy. Moreover, TRIM37 expression was inversely correlated with patient survival in our cohort HCC tissue samples and public HCC database. Overexpression of TRIM37 confers cisplatin resistance on ovarian cancer cells; but, inhibition of TRIM37 sensitized ovarian cancer cell lines to cisplatin cytotoxicity both in vitro and in vivo. Additionally, TRIM37 upregulated the levels of nuclear β-catenin, thereby activating canonical wnt/β-catenin signaling. Conclusions our results demonstrate that targeting TRIM37/β-catenin axis may represent a promising strategy to enhance cisplatin response in patients with chemo-resistant ovarian cancer.

Section: Resultsmentioning

confidence: 99%

WITHDRAWN: Tripartite Motif Containing 37 Activates the Wnt/β-catenin Signalling Pathway and Confers Cisplatin Resistance to Ovarian Carcinoma

Ding

et al. 2020

Preprint

“…TRIM proteins play significant roles in a wide variety of cellular processes including cell cycle, differentiation, apoptosis, autophagy, transcription, DNA repair, innate immunity and anti-viral defense (Hatakeyama, 2017;Venuto & Merla, 2019). As a consequence, mutations of TRIM genes have been implicated in several human diseases such as cancer, auto-immune diseases, rare genetic disorders, infectious diseases and neurodegenerative diseases (Hatakeyama, 2017;Meroni, 2020;Watanabe & Hatakeyama, 2017).…”

Section: Discussionmentioning

confidence: 99%

Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3

Basu-Shrivastava¹,

Mojsa

Mora

et al. 2020

Preprint

NFATc3 is the predominant member of the NFAT family of transcription factor in neurons, where it plays a pro-apoptotic role. Mechanisms controlling NFAT protein stability are poorly understood. Here we identify Trim39 as an E3 ubiquitin-ligase of NFATc3. Indeed, Trim39 ubiquitinates NFATc3 in vitro and in cells, whereas silencing of endogenous Trim39 decreases NFATc3 ubiquitination. We also show that Trim17 inhibits Trim39-mediated ubiquitination of NFATc3 by reducing both the E3 ubiquitin-ligase activity of Trim39 and the NFATc3/Trim39 interaction. Moreover, mutation of SUMOylation sites in NFATc3 or SUMO-interacting motif in Trim39 reduces the NFATc3/Trim39 interaction and Trim39-induced ubiquitination of NFATc3. As a consequence, silencing of Trim39 increases the protein level and transcriptional activity of NFATc3, resulting in enhanced neuronal apoptosis. Likewise, a SUMOylation-deficient mutant of NFATc3 exhibits increased stability and pro-apoptotic activity. Taken together, these data indicate that Trim39 modulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for NFATc3.

“…TRIM family is a group of proteins characterized by three novel functional domains: a 'really interesting new gene' (RING) domain in the N-terminus, 1 or 2 zinc-finger domains called B boxes (B1 box and B2 box) and a coiled-coil motif [11,12]. Due to the specific nature of TRIM proteins, they have been found to be implicated in a variety of biological processes, such as cell proliferation, cell division and developmental processes and cell metabolism [13]. A growing body of evidence shows that several TRIM members are involved in the tumorigenesis and serve as therapeutic targets for the treatment of cancers [14].…”

Section: Discussionmentioning

confidence: 99%

TRIM31 promotes acute myeloid leukemia progression and sensitivity to daunorubicin through the Wnt/β-catenin signaling

Xiao

Deng

et al. 2020

Bioscience Reports

Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment.