scholarly journals The Hh pathway promotes cell apoptosis through Ci-Rdx-Diap1 axis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Bin Liu ◽  
Yan Ding ◽  
Bing Sun ◽  
Qingxin Liu ◽  
Zizhang Zhou ◽  
...  
Keyword(s):  
Birth Defects ◽  
Ubiquitin Ligase ◽  
Cell Apoptosis ◽  
Target Gene ◽  
Regulatory Mechanism ◽  
E3 Ubiquitin Ligase ◽  
Human Diseases ◽  
Induced Apoptosis ◽  
Tumor Drugs ◽  
Transcriptional Target

AbstractApoptosis is a strictly coordinated process to eliminate superfluous or damaged cells, and its deregulation leads to birth defects and various human diseases. The regulatory mechanism underlying apoptosis still remains incompletely understood. To identify novel components in apoptosis, we carry out a modifier screen and find that the Hh pathway aggravates Hid-induced apoptosis. In addition, we reveal that the Hh pathway triggers apoptosis through its transcriptional target gene rdx, which encodes an E3 ubiquitin ligase. Rdx physically binds Diap1 to promote its K63-linked polyubiquitination, culminating in attenuating Diap1−Dronc interaction without affecting Diap1 stability. Taken together, our findings unexpectedly uncover the oncogenic Hh pathway is able to promote apoptosis through Ci-Rdx-Diap1 module, raising a concern to choose Hh pathway inhibitors as anti-tumor drugs.

scholarly journals WSB1 Regulates c-Myc Expression Through β-catenin Signaling and Forms a Feedforward Circuit Promoting the Development of Cancer

2020 ◽  
Author(s):  
Xiaomeng Gao ◽  
Yanling Gong ◽  
Jieqiong You ◽  
Meng Yuan ◽  
Haiying Zhu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Gene ◽  
Regulatory Mechanism ◽  
Intervention Strategy ◽  
E3 Ubiquitin Ligase ◽  
Promoting Effect ◽  
Direct Target Gene ◽  
Direct Target

AbstractThe dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can directly transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies based on its regulatory mechanism hold great potential for cancer therapy. In this study, we found that WSB1, a direct target gene of c-Myc, can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. Luciferase-based promoter activity assays and RNA sequencing results confirmed that WSB1 promoted c-Myc expression through the β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-catenin and subsequently transactivated c-Myc. Of interest, the promoting effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, co-expression of WSB1 and c-Myc strongly enhanced the initiation and progression of tumours both in vitro and in vivo. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

scholarly journals PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP

2017 ◽  
Vol 114 (45) ◽  
pp. 11944-11949 ◽  
Author(s):  
Huibing Wang ◽  
Huyan Meng ◽  
Xingyan Li ◽  
Kezhou Zhu ◽  
Kangyun Dong ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Kinase Activity ◽  
E3 Ubiquitin Ligase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Distinct Cell ◽  
Regulated Expression ◽  
Cell Death Mechanisms ◽  
Induced Apoptosis ◽  
Downstream Mediator

Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show thatPeli1−/−mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.

scholarly journals Molecular Characterization of the Oncogene BTF3 and Its Targets in Colorectal Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Hantao Wang ◽  
Junjie Xing ◽  
Wei Wang ◽  
Guifen Lv ◽  
Haiyan He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Transcription Factor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Rna Seq ◽  
A Subunit ◽  
Cancer Types ◽  
Functional Mechanisms ◽  
Transcriptional Target

Colorectal cancer (CRC) is one of the most commonly diagnosed and leading causes of cancer mortality worldwide, and the prognosis of patients with CRC remains unsatisfactory. Basic transcription factor 3 (BTF3) is an oncogene and hazardous prognosticator in CRC. Although two distinct functional mechanisms of BTF3 in different cancer types have been reported, its role in CRC is still unclear. In this study, we aimed to molecularly characterize the oncogene BTF3 and its targets in CRC. Here, we first identified the transcriptional targets of BTF3 by applying combined RNA-Seq and ChIP-Seq analysis, identifying CHD1L as a transcriptional target of BTF3. Thereafter, we conducted immunoprecipitation (IP)-MS and E3 ubiquitin ligase analysis to identify potential interacting targets of BTF3 as a subunit of the nascent-polypeptide-associated complex (NAC). The analysis revealed that BTF3 might also inhibit E3 ubiquitin ligase HERC2-mediated p53 degradation. Finally, miRNAs targeting BTF3 were predicted and validated. Decreased miR-497-5p expression is responsible for higher levels of BTF3 post-transcriptionally. Collectively, we concluded that BTF3 is an oncogene, and there may exist a transcription factor and NAC-related proteolysis mechanism in CRC. This study provides a comprehensive basis for understanding the oncogenic mechanisms of BTF3 in CRC.

scholarly journals The E3 Ubiquitin Ligase HOIP inhibits Cancer Cell Apoptosis via modulating PTEN stability

2021 ◽  
Vol 12 (21) ◽  
pp. 6553-6562
Author(s):  
Zhiguo Niu ◽  
Xin Li ◽  
Shuxiao Dong ◽  
Jianhui Gao ◽  
Qingsong Huang ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Ubiquitin Ligase ◽  
Cell Apoptosis ◽  
E3 Ubiquitin Ligase ◽  
Cancer Cell Apoptosis

scholarly journals miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase

2020 ◽  
Vol 21 (1) ◽  
pp. 355 ◽  
Author(s):  
Anthea Di Rita ◽  
Teresa Maiorino ◽  
Krenare Bruqi ◽  
Floriana Volpicelli ◽  
Gian Carlo Bellenchi ◽  
...  
Keyword(s):  
Protein Content ◽  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
Feedback Loop ◽  
E3 Ubiquitin Ligase ◽  
Human Diseases ◽  
Mrna Levels ◽  
Cellular Homeostasis ◽  
Promising Therapeutic Target ◽  
Selective Elimination

The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases.

scholarly journals FERONIA phosphorylates E3 ubiquitin ligase ATL6 to modulate the stability of 14-3-3 proteins in response to the carbon/nitrogen ratio

2019 ◽  
Vol 70 (21) ◽  
pp. 6375-6388 ◽  
Author(s):  
Guoyun Xu ◽  
Weijun Chen ◽  
Limei Song ◽  
Qiansi Chen ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Regulatory Mechanism ◽  
E3 Ubiquitin Ligase ◽  
Receptor Kinase ◽  
Carbon Nitrogen Ratio ◽  
Nitrogen Ratio ◽  
The Stability

This study reveals a novel regulatory mechanism that links the versatile receptor kinase FERONIA with plant C/N responses.

The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2

2009 ◽  
Vol 11 (12) ◽  
pp. 1411-1420 ◽  
Author(s):  
Agnieszka Rybak ◽  
Heiko Fuchs ◽  
Kamyar Hadian ◽  
Lena Smirnova ◽  
Ellery A. Wulczyn ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ubiquitin Ligase ◽  
Target Gene ◽  
E3 Ubiquitin Ligase ◽  
Mirna Pathway

scholarly journals pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation

2021 ◽  
Author(s):  
Caixia Wang ◽  
Xiaozhi Rong ◽  
Haifeng Zhang ◽  
Bo Wang ◽  
Yan Bai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Protein Stability ◽  
Ubiquitin Ligase ◽  
Target Gene ◽  
E3 Ubiquitin Ligase ◽  
Proteasomal Degradation ◽  
26S Proteasome ◽  
Cell Fate Decisions ◽  
Target Gene Expression

The Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting β-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/β-catenin signaling.

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