Decreased TOB1 expression and increased phosphorylation of nuclear TOB1 promotes gastric cancer

Guan, Rongwei; Peng, Lei; Wang, Dong; He, Hongjie; Wang, Dexu; Zhang, Rui; Wang, Hui; Hao, Huiting; Zhang, Jian; Song, He; Sui, Shuning; Meng, Xin; Cui, Xiaobo; Bai, Jing; Sun, Wenjing; Fu, Songbin; Yu, Jingcui

doi:10.18632/oncotarget.20749

Cited by 14 publications

(14 citation statements)

References 19 publications

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“…Another way of transmitting ERK-dependent nuclear activity is by inhibition of tumor suppressor proteins, and example for such mechanism is Tob [ 78 ]. This transcriptional suppressor demonstrates antiproliferative function by binding to transcription factors in the nucleus and suppressing the expression of cyclin D1 and other regulatory genes [ 79 , 80 ]. Importantly, ERK phosphorylates Tob in the nucleus on Sers 152, 154, and 164 and these phosphorylations inhibit Tob activation and may support carcinogenesis [ 81 ].…”

Section: Nuclear Substrates Of Erk In Cancer Development and Maintmentioning

confidence: 99%

Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer

Maik-Rachline

Hacohen-Lev-Ran

Seger

2019

IJMS

155

100

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The extracellular signal-regulated kinases 1/2 (ERK) are central signaling components that regulate stimulated cellular processes such as proliferation and differentiation. When dysregulated, these kinases participate in the induction and maintenance of various pathologies, primarily cancer. While ERK is localized in the cytoplasm of resting cells, many of its substrates are nuclear, and indeed, extracellular stimulation induces a rapid and robust nuclear translocation of ERK. Similarly to other signaling components that shuttle to the nucleus upon stimulation, ERK does not use the canonical importinmechanism of nuclear translocation. Rather, it has its own unique nuclear translocation signal (NTS) that interacts with importin7 to allow stimulated shuttling via the nuclear pores. Prevention of the nuclear translocation inhibits proliferation of B-Raf- and N/K-Ras-transformed cancers. This effect is distinct from the one achieved by catalytic Raf and MEK inhibitors used clinically, as cells treated with the translocation inhibitors develop resistance much more slowly. In this review, we describe the mechanism of ERK translocation, present all its nuclear substrates, discuss its role in cancer and compare its translocation to the translocation of other signaling components. We also present proof of principle data for the use of nuclear ERK translocation as an anti-cancer target. It is likely that the prevention of nuclear ERK translocation will eventually serve as a way to combat Ras and Raf transformed cancers with less side-effects than the currently used drugs.

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Section: Nuclear Substrates Of Erk In Cancer Development and Maintmentioning

confidence: 99%

Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer

Maik-Rachline

Hacohen-Lev-Ran

Seger

2019

IJMS

155

100

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“…Our results showed that CXCR4 , DDIT4 , and TOB1 were the highest before occluder treatment and downregulated after treatment with both PLLA and metal device. Previous studies demonstrated that DDIT4 regulates cell growth, proliferation, and survival by inhibiting the activity of mammalian mTORC1 targets ( Wang et al, 2015 ), while TOB1 , as an anti-proliferative gene, can regulate cell growth and differentiation and has a migratory role ( Liu et al, 2015 ; Guan et al, 2017 ; Shangguan et al, 2019 ). Finally, we also confirmed that CXCR4 is a candidate gene responsible for cardiac congenital pathologies in human as previously suggested in mouse studies ( Escot et al, 2013 ; Wang et al, 2014 ; Zhong and Rajagopalan, 2015 ; Page et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Key Regulatory Differentially Expressed Genes in the Blood of Atrial Septal Defect Children Treated With Occlusion Devices

Tang

Yue-jin

et al. 2021

Front. Genet.

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Atrial septal defects (ASDs) are the most common types of cardiac septal defects in congenital heart defects. In addition to traditional therapy, interventional closure has become the main treatment method. However, the molecular events and mechanisms underlying the repair progress by occlusion device remain unknown. In this study, we aimed to characterize differentially expressed genes (DEGs) in the blood of patients treated with occlusion devices (metal or poly-L-lactic acid devices) using RNA-sequencing, and further validated them by qRT-PCR analysis to finally determine the expression of key mediating genes after closure of ASD treatment. The result showed that total 1,045 genes and 1,523 genes were expressed differently with significance in metal and poly-L-lactic acid devices treatment, respectively. The 115 overlap genes from the different sub-analyses are illustrated. The similarities and differences in gene expression reflect that the body response process involved after interventional therapy for ASDs has both different parts that do not overlap and the same part that crosses. The same portion of body response regulatory genes are key regulatory genes expressed in the blood of patients with ASDs treated with closure devices. The gene ontology enrichment analysis showed that biological processes affected in metal device therapy are immune response with CXCR4 genes and poly-L-lactic acid device treatment, and the key pathways are nuclear-transcribed mRNA catabolic process and proteins targeting endoplasmic reticulum process with ribosomal proteins (such as RPS26). We confirmed that CXCR4, TOB1, and DDIT4 gene expression are significantly downregulated toward the pre-therapy level after the post-treatment in both therapy groups by qRT-PCR. Our study suggests that the potential role of CXCR4, DDIT4, and TOB1 may be key regulatory genes in the process of endothelialization in the repair progress of ASDs, providing molecular insights into this progress for future studies.

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“…Recently, we identified that decreased TOB1 expression and increased nuclear phosphorylated TOB1 were associated with aggressive tumor behavior and a poor prognosis in intestinal type GC. Additionally, TOB1 nuclear retention is critical for its anti-proliferative activity in vitro 16 .…”

Section: Discussionmentioning

confidence: 99%

“…To date, an increasing number of researches focus on the role of TOB1 in gastric cancerogenesis, which including the localization and expression of the gene 13 - 15 , the mechanisms of inactivation, tumor suppressor involving the participating pathways, and its effect in the cell cycle, etc. 16 , 28 , 38 . A new study reported that TOB1 gene was contribute to estrogen-independent breast cancer and the interaction effects between TOB1 gene with AKT/mTOR survival signaling 39 .…”

Section: Discussionmentioning

confidence: 99%

“…Then, we demonstrated that the down-regulation of TOB1 expression and the accumulation of phosphorylated TOB1 promoted carcinogenesis in four GC cell lines and tissue specimens from 97 patients with primary GC 15 . Furthermore, we identified that decreased TOB1 expression and increased phosphorylation of nuclear TOB1 were associated with a malignant tumor phenotype and poor survival in 341 primary GC patients 16 .…”

Section: Introductionmentioning

confidence: 98%

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Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China

et al. 2018

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The TOB1 (ErbB-2,1) gene is an anti-proliferative factor that has the potential to regulate cell growth and encodes a member of the transducer of erbB-2/B-cell translocation gene protein. The association between the polymorphisms of the TOB1 gene and gastric cancer (GC) risk is still unclear. In this study, 506 GC cases and 548 healthy controls (HCs) were collected to evaluate the association between the eleven SNPs (rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976 and rs4626) of the TOB1 gene and GC risk in the population of northeast China. The results showed that there were significant associations of haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC with GC risk (P < 0.05, P < 0.001, and P <0.001, respectively). The association between rs12601477 GA+AA genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.53, 95% CI=1.05-2.22, P< 0.05). The association between rs4626 AG+GG genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.54, 95% CI = 1.03-2.28, P<0.05). The rs34700818 CT+TT genotypes were associated with a significantly increased risk of T3-T4 (CT+TT vs CC, adjusted OR=1.71, 95% CI= 1.01-2.88, P<0.05) and TNM stage II (CT+TT vs CC, adjusted OR=2.40, 95% CI =1.27-4.52, P<0.01). The rs61482741 CG+GG genotypes were also associated with a significantly increased risk of T3-T4 (CG+GG vs CC, adjusted OR=1.71, 95% CI = 1.01-2.88, P<0.05) and TNM stage II (CG+GG vs CC, adjusted OR=2.40, 95% CI=1.27-4.52, P<0.01). The results suggest that four SNPs (rs12601477, rs4626, rs34700818 and rs61482741) of the TOB1 gene play an important role in the occurrence and development of GC in the Chinese Han population of northeast China.

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Decreased TOB1 expression and increased phosphorylation of nuclear TOB1 promotes gastric cancer

Cited by 14 publications

References 19 publications

Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer

Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer

Key Regulatory Differentially Expressed Genes in the Blood of Atrial Septal Defect Children Treated With Occlusion Devices

Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China

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