scholarly journals CRL4DCAF1/VprBP E3 ubiquitin ligase controls ribosome biogenesis, cell proliferation, and development

2020 ◽  
Vol 6 (51) ◽  
pp. eabd6078
Author(s):  
Xiao-Ran Han ◽  
Naoya Sasaki ◽  
Sarah C. Jackson ◽  
Pu Wang ◽  
Zhijun Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Molecular Basis ◽  
Ribosome Biogenesis ◽  
E3 Ubiquitin Ligase ◽  
Proliferating Cells ◽  
Critical Function ◽  
Assembly Factor ◽  
P53 Activation ◽  
Quiescent T Cells

Evolutionarily conserved DCAF1 is a major substrate receptor for the DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4) and controls cell proliferation and development. The molecular basis for these functions is unclear. We show here that DCAF1 loss in multiple tissues and organs selectively eliminates proliferating cells and causes perinatal lethality, thymic atrophy, and bone marrow defect. Inducible DCAF1 loss eliminates proliferating, but not quiescent, T cells and MEFs. We identify the ribosome assembly factor PWP1 as a substrate of the CRL4DCAF1 ligase. DCAF1 loss results in PWP1 accumulation, impairing rRNA processing and ribosome biogenesis. Knockdown or overexpression of PWP1 can rescue defects or cause similar defects as DCAF1 loss, respectively, in ribosome biogenesis. DCAF1 loss increases free RPL11, resulting in L11-MDM2 association and p53 activation. Cumulatively, these results reveal a critical function for DCAF1 in ribosome biogenesis and define a molecular basis of DCAF1 function in cell proliferation and development.

scholarly journals A means to an end: ubiquitination of Mpl

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1111-1112
Author(s):  
Wei Tong
Keyword(s):  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Down Regulation

Abstract In this issue of Blood, Saur and colleagues report that ubiquitin-mediated degradation of the Mpl receptor constrains Tpo-mediated cell proliferation, highlighting the importance of the E3 ubiquitin ligase c-Cbl in rapid down-regulation of Tpo/Mpl signaling.

scholarly journals Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP

2012 ◽  
Vol 444 (3) ◽  
pp. 581-590 ◽  
Author(s):  
Xue-Yuan Dong ◽  
Xiaoying Fu ◽  
Songqing Fan ◽  
Peng Guo ◽  
Dan Su ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Feedback Loop ◽  
E3 Ubiquitin Ligase ◽  
Breast Development ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Dependent Cell ◽  
Proteasome Pathway

We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen–ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen–ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin–proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen–ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.

scholarly journals Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development

2021 ◽  
Vol 22 (21) ◽  
pp. 11875
Author(s):  
Fang Hua ◽  
Wenzhuo Hao ◽  
Lingyan Wang ◽  
Shitao Li
Keyword(s):  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Tumor Development ◽  
E3 Ubiquitin Ligase ◽  
Growth Factor Receptor ◽  
Ubiquitin Chain ◽  
Plakophilin 2 ◽  
Ubiquitin Ligase Activity ◽  
Signaling Axis ◽  
Differentiation And Proliferation

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR and that perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.

scholarly journals HELZ2 Promotes K63-Linked Polyubiquitination of c-Myc to Induce Retinoblastoma Tumorigenesis

2021 ◽  
Author(s):  
Hanjun Dai ◽  
wen ZENG ◽  
WEIJUAN ZENG ◽  
MING YAN ◽  
ping jiang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Zinc Finger ◽  
Ubiquitin Ligase ◽  
Critical Role ◽  
E3 Ubiquitin Ligase ◽  
Transcriptional Regulators ◽  
Zinc Finger Domain ◽  
Retinoblastoma Cell ◽  
Animal Survival

Abstract Retinoblastoma is a rare ocular tumor in children that originates in the retina. Several core transcriptional regulators maintain the expansion of retinoblastoma tumors, including c-Myc. Here, we demonstrated that Helicase with zinc finger domain 2 (HELZ2) promoted retinoblastoma tumorigenesis by targeting c-Myc. HELZ2-deficient inhibited retinoblastoma cell proliferation, whereas overexpression of HELZ2 promoted retinoblastoma cell proliferation. In addition, high levels of HELZ2 promoted xenograft retinoblastoma tumorigenesis and inhibited animal survival. Mechanistically, HELZ2 interacted with c-Myc and promoted its K63-linked polyubiquitination. We indicated that HELZ2 promoted the interaction between E3 ubiquitin ligase HUWE1 and c-Myc, and HELZ2-mediated K63-linked polyubiquitination and activation of c-Myc were dependent on HUWE1. Taken together, HELZ2 plays a critical role in the regulation of retinoblastoma tumorigenesis by enhancing the activity of c-Myc.

scholarly journals RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tingting Li ◽  
Xian Wang ◽  
Enguo Ju ◽  
Suzane Ramos da Silva ◽  
Luping Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cell Types ◽  
Alternative Mechanism ◽  
Central Controller ◽  
Low Levels ◽  
Mtorc1 Activation

AbstractmTORC1, a central controller of cell proliferation in response to growth factors and nutrients, is dysregulated in cancer. Whereas arginine activates mTORC1, it is overridden by high expression of cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Because cancer cells often encounter low levels of nutrients, an alternative mechanism might exist to regulate CASTOR1 expression. Here we show K29-linked polyubiquitination and degradation of CASTOR1 by E3 ubiquitin ligase RNF167. Furthermore, AKT phosphorylates CASTOR1 at S14, significantly increasing its binding to RNF167, and hence its ubiquitination and degradation, while simultaneously decreasing its affinity to MIOS, leading to mTORC1 activation. Therefore, AKT activates mTORC1 through both TSC2- and CASTOR1-dependent pathways. Several cell types with high CASTOR1 expression are insensitive to arginine regulation. Significantly, AKT and RNF167-mediated CASTOR1 degradation activates mTORC1 independent of arginine and promotes breast cancer progression. These results illustrate a mTORC1 regulating mechanism and identify RNF167 as a therapeutic target for mTORC1-dysregulated diseases.

scholarly journals Competitive ubiquitination activates the tumor suppressor p53

2019 ◽  
Vol 27 (6) ◽  
pp. 1807-1818 ◽  
Author(s):  
Xingyao Li ◽  
Mengqi Guo ◽  
Lun Cai ◽  
Tingting Du ◽  
Ying Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Catalytic Activity ◽  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Activating Transcription Factor 3 ◽  
Tumor Suppressor P53 ◽  
Unknown Mechanism ◽  
P53 Activation ◽  
Activating Transcription Factor

AbstractBlocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin “trap” and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.

scholarly journals Retroviral insertional mutagenesis implicates E3 ubiquitin ligase RNF168 in the control of cell proliferation and survival

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Aytug Kizilors ◽  
Mark R. Pickard ◽  
Cathleen E. Schulte ◽  
Kiren Yacqub-Usman ◽  
Nicola J. McCarthy ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Line ◽  
Cell Fate ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Nuclear Bodies ◽  
Forward Genetics ◽  
Dna Breaks ◽  
Control Of Gene Expression ◽  
Pml Nuclear Bodies

The E3 ubiquitin ligase RNF168 is a ring finger protein that has been previously identified to play an important regulatory role in the repair of double-strand DNA breaks. In the present study, an unbiased forward genetics functional screen in mouse granulocyte/macrophage progenitor cell line FDCP1 has identified E3 ubiquitin ligase RNF168 as a key regulator of cell survival and proliferation. Our data indicate that RNF168 is an important component of the mechanisms controlling cell fate, not only in human and mouse haematopoietic growth factor dependent cells, but also in the human breast epithelial cell line MCF-7. These observations therefore suggest that RNF168 provides a connection to key pathways controlling cell fate, potentially through interaction with PML nuclear bodies and/or epigenetic control of gene expression. Our study is the first to demonstrate a critical role for RNF168 in the mechanisms regulating cell proliferation and survival, in addition to its well-established role in DNA repair.

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