Ubiquitination of p21 by E3 Ligase TRIM21 Promotes the Proliferation of Human Neuroblastoma Cells

Wang, Fan; Wu, Zerui; Li, Qun; Ni, Zhihui; Wang, Chengde; Lu, Jianglong

doi:10.1007/s12017-021-08661-3

Cited by 7 publications

(6 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TRIM21, an autoantigen that presents in patients with systemic lupus erythematosus (SLE), encodes for a ubiquitously expressed protein known as RING dependent E3 ligase that can be detected in the cell cytoplasm and nucleus 34 . It also promoted 35 or impeded 36 , 37 cancer progression via ubiquitination of target cancer-related proteins and releasing DNA mitochondrial 6 TRIM21 was also reported to promote invasion and radiotherapy resistance in glioma 38 , 39 . Herein, we determined that TRIM21 facilitated the progression of GBM in vitro and in vivo via its RING-dependent E3 ligase activity, and that PRYSPRY domain of TRIM21, was critical for the interaction with TIF1γ and its degradation.…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma

Li,

Bao,

Zheng

et al. 2023

Theranostics

View full text Add to dashboard Cite

Background: Elucidation of the mechanism of ubiquitation has led to novel ways to treat glioblastoma (GBM). A tripartite motif (TRIM) protein mediates a reversible, stringent ubiquitation which is closely related to glioma malignancy. This study intends to screen the most vital and abnormal regulating component of the tripartite motif protein and to explore its underlying mechanisms. Methods: TRIM21 is identified as an important oncogene that accelerates the progression of glioma cell through database in a multidimensional way and this is confirmed in human samples and cells. Tandem Mass Tags (TMT) and MS analysis are performed to discover the substrates of TRIM21.The underlying mechanisms are further investigated by CO-IP, luciferase reporter assays and gain and loss of function assays. In vivo treatment with siRNA is applied to evaluate the therapeutic significance of TRIM21. Result: We screened a panel of TRIM proteins and identified TRIM21, a E3 ubiquitin-protein ligase and autoantigen, as well as a prognostic biomarker for GBM. Functionally, high expression of wild-type TRIM21 accelerates tumor progression in vitro and in vivo , whereas TRIM21 mutants, including one with a critical RING-finger deletion, do not. Mechanistically, TRIM21 stimulates K63-linked ubiquitination and subcellular translocation of active β-catenin from the cytoplasm to the nucleus. Moreover, TRIM21 forms a complex with the β-catenin upstream regulator, TIF1γ, in the nucleus and accelerated its degradation by inducing K48-linked ubiquitination at K5 site, consequently increasing further nuclear β-catenin presence. Endogenous TRIM21 levels are found to be inversely correlated with TIF1γ but positively correlated with β-catenin in glioma tissue microarray experiments. Furthermore, direct injection of TRIM21 small interfering RNA (siRNA) into U87 cell-derived tumors (in vivo treatment with siRNA) is proved to inhibit tumor growth in nude mice. Conclusion: This work suggests that TRIM21/TIF1γ/β-catenin axis is involved in the progression of human GBM. TRIM21 is a promising therapeutic and prognostic biomarker for glioma with hyperactive β-catenin.

show abstract

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma

Li,

Bao,

Zheng

et al. 2023

Theranostics

View full text Add to dashboard Cite

show abstract

“…TRIM21 can not only regulate tumor metabolic process, immune function and tumor treatment, it is also a useful cancer prognostic indicator, but the cancer type needs to be defined. TRIM21 expression is downregulated and correlated with shorter overall survival in patients with hepatocellular carcinoma (145) and diffuse large B cell lymphoma (19), while high expression of TRIM21 is correlated with poorer clinical outcomes in glioma (119), pancreatic cancer (110, 146), soft tissue sarcoma (147) and esophageal squamous cell carcinoma (148).…”

Section: Discussionmentioning

confidence: 99%

“…The underlying regulatory mechanisms may vary determined in different cancer types. TRIM21 induces the accumulation of p21 in ovarian carcinoma (105), but directly induce the ubiquitination of p21 in neuroblastoma (119). TRIM21 can also decrease p21 expression in an indirect manner via post-translational regulation of thioredoxin-interacting protein (TXNIP) in osteosarcoma (120).…”

Section: Role Of Trim21 In Cancer Treatmentmentioning

confidence: 99%

The emerging roles of TRIM21 in coordinating cancer metabolism, immunity and cancer treatment

et al. 2022

View full text Add to dashboard Cite

Tripartite motif containing-21 (TRIM21), an E3 ubiquitin ligase, was initially found to be involved in antiviral responses and autoimmune diseases. Recently studies have reported that TRIM21 plays a dual role in cancer promoting and suppressing in the occurrence and development of various cancers. Despite the fact that TRIM21 has effects on multiple metabolic processes, inflammatory responses and the efficacy of tumor therapy, there has been no systematic review of these topics. Herein, we discuss the emerging role and function of TRIM21 in cancer metabolism, immunity, especially the immune response to inflammation associated with tumorigenesis, and also the cancer treatment, hoping to shine a light on the great potential of targeting TRIM21 as a therapeutic target.

show abstract

“…These results suggest that YTHDF2 is presumably involved in m 6 A-mediated regulation of ubiquitination pathway. TRIM21 E3 ligase promotes p21 ubiquitination in human neuroblastoma cells (Wang et al 2021). To explore whether TRIM21 is involved in DONinduced decline in p21 ubiquitination in HT-22 cells, we determined TRIM21 mRNA and conducted its mRNA decay assay.…”

Section: Don-induced Inhibition Of Ht-22 Cell Proliferation Requires ...mentioning

confidence: 99%

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Xu,

Zhao,

Feng

et al. 2024

Cell Biol Toxicol

View full text Add to dashboard Cite

Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m6A methylation levels on the 3’UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6A readers YTHDF1 and IGF2BP1 are responsible for m6A-mediated increase in p21 mRNA stability. Meanwhile, 3’UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6A hypermethylated, and another m6A reader YTHDF2 binds to the m6A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases. Graphical abstract DON inhibits the proliferation of HT-22 cells. RNA m6A hypermethylation on the transcript of p21 enhances the mRNA stability in a YTHDF1- and IGF2BP1-dependent manner, which leads to the upregulation of p21. RNA m6A hypermethylation on the transcript of TRIM21 decreases the mRNA stability in a YTHDF2-dependent manner, which contributes to prevent p21 ubiquitin-mediated degradation. High expression of p21 contributes to inhibit cell proliferation.

show abstract

Ubiquitination of p21 by E3 Ligase TRIM21 Promotes the Proliferation of Human Neuroblastoma Cells

Cited by 7 publications

References 24 publications

E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma

E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma

The emerging roles of TRIM21 in coordinating cancer metabolism, immunity and cancer treatment

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Contact Info

Product

Resources

About