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.

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 IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation

2018 ◽  
Vol 2 (5) ◽  
pp. 492-504 ◽  
Author(s):  
Shirong Li ◽  
Jing Fu ◽  
Hui Wang ◽  
Huihui Ma ◽  
Xiaoming Xu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cd34 Cells ◽  
Key Points

Key Points IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase. Loss of IKZF1 is associated with a decrease of PU.1, critical for the development and maturation of neutrophils.

scholarly journals RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
John J. Krais ◽  
Yifan Wang ◽  
Pooja Patel ◽  
Jayati Basu ◽  
Andrea J. Bernhardy ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Coiled Coil ◽  
Histone H2a ◽  
Dna Breaks ◽  
Diverse Range ◽  
Dna Damage Signaling ◽  
Dna Repair Proteins ◽  
K 13

AbstractDNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168− and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.

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 Regulation of photoprotection gene expression in Chlamydomonas by a putative E3 ubiquitin ligase complex and a homolog of CONSTANS

2019 ◽  
Vol 116 (35) ◽  
pp. 17556-17562 ◽  
Author(s):  
Stéphane T. Gabilly ◽  
Christopher R. Baker ◽  
Setsuko Wakao ◽  
Thien Crisanto ◽  
Katharine Guan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
High Light ◽  
Forward Genetics ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Low Light ◽  
Green Algal ◽  
Ubiquitin Ligase Complex

Photosynthetic organisms use nonphotochemical quenching (NPQ) mechanisms to dissipate excess absorbed light energy and protect themselves from photooxidation. In the model green alga Chlamydomonas reinhardtii, the capacity for rapidly reversible NPQ (qE) is induced by high light, blue light, and UV light via increased expression of LHCSR and PSBS genes that are necessary for qE. Here, we used a forward genetics approach to identify SPA1 and CUL4, components of a putative green algal E3 ubiquitin ligase complex, as critical factors in a signaling pathway that controls light-regulated expression of the LHCSR and PSBS genes in C. reinhardtii. The spa1 and cul4 mutants accumulate increased levels of LHCSR1 and PSBS proteins in high light, and unlike the wild type, they express LHCSR1 and exhibit qE capacity even when grown in low light. The spa1-1 mutation resulted in constitutively high expression of LHCSR and PSBS RNAs in both low light and high light. The qE and gene expression phenotypes of spa1-1 are blocked by mutation of CrCO, a B-box Zn-finger transcription factor that is a homolog of CONSTANS, which controls flowering time in plants. CONSTANS-like cis-regulatory sequences were identified proximal to the qE genes, consistent with CrCO acting as a direct activator of qE gene expression. We conclude that SPA1 and CUL4 are components of a conserved E3 ubiquitin ligase that acts upstream of CrCO, whose regulatory function is wired differently in C. reinhardtii to control qE capacity via cis-regulatory CrCO-binding sites at key photoprotection genes.

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