scholarly journals The tumor suppressor archipelago E3 ligase is required for spermatid differentiation in Drosophila testis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Viktor Vedelek ◽  
Attila L. Kovács ◽  
Gábor Juhász ◽  
Elham Alzyoud ◽  
Rita Sinka
Keyword(s):  
Tumor Suppressor ◽  
Mitochondrial Morphology ◽  
Male Sterile ◽  
Tissue Specific ◽  
Cellular Processes ◽  
Ubiquitin Ligase Complex ◽  
Drosophila Testis ◽  
Human Orthologue ◽  
F Box Protein ◽  
Multiple Abnormalities

AbstractThe human orthologue of the tumor suppressor protein FBW7 is encoded by the Drosophila archipelago (ago) gene. Ago is an F-box protein that gives substrate specificity to its SCF ubiquitin ligase complex. It has a central role in multiple biological processes in a tissue-specific manner such as cell proliferation, cellular differentiation, hypoxia-induced gene expression. Here we present a previously unknown tissue-specific role of Ago in spermatid differentiation. We identified a classical mutant of ago which is semi-lethal and male-sterile. During the characterization of ago function in testis, we found that ago plays role in spermatid development, following meiosis. We confirmed spermatogenesis defects by silencing ago by RNAi in testes. The ago mutants show multiple abnormalities in elongating and elongated spermatids, including aberration of the cyst morphology, malformed mitochondrial structures, and individualization defects. Additionally, we determined the subcellular localization of Ago protein with mCherry-Ago transgene in spermatids. Our findings highlight the potential roles of Ago in different cellular processes of spermatogenesis, like spermatid individualization, and regulation of mitochondrial morphology.

scholarly journals FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Michael Schieber ◽  
Christian Marinaccio ◽  
Lyndsey C. Bolanos ◽  
Wendy D. Haffey ◽  
Kenneth D. Greis ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Leukemic Transformation ◽  
Secondary Acute Myeloid Leukemia ◽  
Ubiquitin Ligase Complex ◽  
Genetic Abnormalities ◽  
Scf Ubiquitin Ligase ◽  
Cellular Pathways ◽  
F Box Protein

Abstract Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.

scholarly journals Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21

2015 ◽  
Vol 112 (50) ◽  
pp. 15372-15377 ◽  
Author(s):  
Cuiyan Zhang ◽  
Xiaotong Li ◽  
Guillaume Adelmant ◽  
Jessica Dobbins ◽  
Christoph Geisen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Family Members ◽  
Binding Motif ◽  
Retinoblastoma Tumor Suppressor ◽  
Ubiquitin Ligase Complex ◽  
Retinoblastoma Tumor ◽  
F Box Protein ◽  
Necessary And Sufficient

EP300-interacting inhibitor of differentiation 1 (EID1) belongs to a protein family implicated in the control of transcription, differentiation, DNA repair, and chromosomal maintenance. EID1 has a very short half-life, especially in G0 cells. We discovered that EID1 contains a peptidic, modular degron that is necessary and sufficient for its polyubiquitylation and proteasomal degradation. We found that this degron is recognized by an Skp1, Cullin, and F-box (SCF)-containing ubiquitin ligase complex that uses the F-box Only Protein 21 (FBXO21) as its substrate recognition subunit. SCFFBXO21 polyubiquitylates EID1 both in vitro and in vivo and is required for the efficient degradation of EID1 in both cycling and quiescent cells. The EID1 degron partially overlaps with its retinoblastoma tumor suppressor protein-binding domain and is congruent with a previously defined melanoma-associated antigen-binding motif shared by EID family members, suggesting that binding to retinoblastoma tumor suppressor and melanoma-associated antigen family proteins could affect the polyubiquitylation and turnover of EID family members in cells.

scholarly journals Nonredundant Roles of Mitochondria-associated F-Box Proteins Mfb1 and Mdm30 in Maintenance of Mitochondrial Morphology in Yeast

2006 ◽  
Vol 17 (9) ◽  
pp. 3745-3755 ◽  
Author(s):  
Mark Dürr ◽  
Mafalda Escobar-Henriques ◽  
Sandra Merz ◽  
Stefan Geimer ◽  
Thomas Langer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Mitochondrial Inheritance ◽  
Physiological Conditions ◽  
Cellular Processes ◽  
Protein Mutants ◽  
Homozygous Diploid ◽  
F Box Protein

Mitochondria constantly fuse and divide to adapt organellar morphology to the cell’s ever-changing physiological conditions. Little is known about the molecular mechanisms regulating mitochondrial dynamics. F-box proteins are subunits of both Skp1-Cullin-F-box (SCF) ubiquitin ligases and non-SCF complexes that regulate a large number of cellular processes. Here, we analyzed the roles of two yeast F-box proteins, Mfb1 and Mdm30, in mitochondrial dynamics. Mfb1 is a novel mitochondria-associated F-box protein. Mitochondria in mutants lacking Mfb1 are fusion competent, but they form aberrant aggregates of interconnected tubules. In contrast, mitochondria in mutants lacking Mdm30 are highly fragmented due to a defect in mitochondrial fusion. Fragmented mitochondria are docked but nonfused in Δmdm30 cells. Mitochondrial fusion is also blocked during sporulation of homozygous diploid mutants lacking Mdm30, leading to a mitochondrial inheritance defect in ascospores. Mfb1 and Mdm30 exert nonredundant functions and likely have different target proteins. Because defects in F-box protein mutants could not be mimicked by depletion of SCF complex and proteasome core subunits, additional yet unknown factors are likely involved in regulating mitochondrial dynamics. We propose that mitochondria-associated F-box proteins Mfb1 and Mdm30 are key components of a complex machinery that regulates mitochondrial dynamics throughout yeast’s entire life cycle.

scholarly journals An UBR-box from a non-N-recognin: Crystal Structure of the UBR domain of UBR6

2014 ◽  
Vol 70 (a1) ◽  
pp. C306-C306
Author(s):  
Juliana Muñoz-Escobar ◽  
Guennadi Kozlov ◽  
Jean-François Trempe ◽  
Kalle Gehring
Keyword(s):  
Crystal Structure ◽  
Ubiquitin Proteasome System ◽  
Zinc Binding ◽  
Binding Motifs ◽  
Clear Explanation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Binding Pockets ◽  
F Box Protein

The degradation of many short-lived proteins in eukaryotic cells is carried out by the Ubiquitin Proteasome System. The N-end rule pathway links the half-life of proteins to the identity of its N-terminal residue, also called N-degron. Destabilizing N-degrons, are recognized by E3 ubiquitin ligases termed N-recognins. N-degrons are grouped into type 1, composed of basic residues, and type 2, composed of bulky hydrophobic residues. In mammals, four N-recognins mediate the N-end rule pathway: UBR1, UBR2, UBR4 and UBR5. These proteins share a ~70-residue zinc finger-like motif termed the Ubiquitin Recognin (UBR) box, responsible for their specificity. The mammalian genome encodes at least three more UBR-box proteins: UBR3, UBR6/FBXO11 and UBR7. However, these UBRs cannot recognize any type of N-degrons. Our lab reported the crystal structures of the UBR boxes from the human UBR1 and UBR2, rationalizing the empirical rules for the classification of type 1 N-degrons. Despite the valuable information obtained from those structures there is not a clear explanation for the no recognition of N-degrons by other UBR-box proteins. Here we report the crystal structure of the UBR-box domain from UBR6 also known as FBXO11. UBR6 is a F-box protein of the SKP1-Cullin1-F-box (SCF) ubiquitin ligase complex and does not recognize any type of N-degrons. We crystallized a 77-residue fragment of the UBR-box of UBR6 and determined its structure at 1.7 Å resolution. Unexpectedly, this domain adopts an open conformation compared to UBR1-box, without any N-degron binding pockets. Its zinc-binding residues are conserved as in the N-recognins, but they are arranged in different zinc-binding motifs. Molecules form dimmers stabilized by zinc ions. The crystal had 4 molecules per asymmetric unit and space group P212121. For phasing we used Zn-SAD. With this structure we hope to obtain clues that explain the absence of N-degron recognition in some members of the UBR family.

scholarly journals CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene

2021 ◽  
Vol 11 ◽  
Author(s):  
Zainab A. Bazzi ◽  
Isabella T. Tai
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Kinase Activity ◽  
Screening Assay ◽  
Cellular Processes ◽  
Molecule Inhibitor ◽  
High Throughput Screening Assay ◽  
Kinase Activity Assay

Cyclin-dependent kinase 10 (CDK10) is a CDC2-related serine/threonine kinase involved in cellular processes including cell proliferation, transcription regulation and cell cycle regulation. CDK10 has been identified as both a candidate tumor suppressor in hepatocellular carcinoma, biliary tract cancers and gastric cancer, and a candidate oncogene in colorectal cancer (CRC). CDK10 has been shown to be specifically involved in modulating cancer cell proliferation, motility and chemosensitivity. Specifically, in CRC, it may represent a viable biomarker and target for chemoresistance. The development of therapeutics targeting CDK10 has been hindered by lack a specific small molecule inhibitor for CDK10 kinase activity, due to a lack of a high throughput screening assay. Recently, a novel CDK10 kinase activity assay has been developed, which will aid in the development of small molecule inhibitors targeting CDK10 activity. Discovery of a small molecular inhibitor for CDK10 would facilitate further exploration of its biological functions and affirm its candidacy as a therapeutic target, specifically for CRC.

scholarly journals Improved detection of tumor suppressor events in single-cell RNA-Seq data

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Andrew E. Teschendorff ◽  
Ning Wang
Keyword(s):  
Transcription Factors ◽  
Tumor Suppressor ◽  
Single Cell ◽  
Cancer Cells ◽  
Dropout Rate ◽  
Lung Epithelial Cells ◽  
Rna Seq ◽  
Regulatory Activity ◽  
Tissue Specific ◽  
Early Tumor

Abstract Tissue-specific transcription factors are frequently inactivated in cancer. To fully dissect the heterogeneity of such tumor suppressor events requires single-cell resolution, yet this is challenging because of the high dropout rate. Here we propose a simple yet effective computational strategy called SCIRA to infer regulatory activity of tissue-specific transcription factors at single-cell resolution and use this tool to identify tumor suppressor events in single-cell RNA-Seq cancer studies. We demonstrate that tissue-specific transcription factors are preferentially inactivated in the corresponding cancer cells, suggesting that these are driver events. For many known or suspected tumor suppressors, SCIRA predicts inactivation in single cancer cells where differential expression does not, indicating that SCIRA improves the sensitivity to detect changes in regulatory activity. We identify NKX2-1 and TBX4 inactivation as early tumor suppressor events in normal non-ciliated lung epithelial cells from smokers. In summary, SCIRA can help chart the heterogeneity of tumor suppressor events at single-cell resolution.

scholarly journals N6-Isopentenyladenosine Inhibits Colorectal Cancer and Improves Sensitivity to 5-Fluorouracil Targeting FBXW7 Tumor Suppressor

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1456 ◽  
Author(s):  
Donatella Fiore ◽  
Chiara Piscopo ◽  
Maria Proto ◽  
Michele Vasaturo ◽  
Fabrizio Dal Piaz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
In Vitro Models ◽  
Antitumor Action ◽  
Cancer Proliferation ◽  
Ubiquitinated Proteins ◽  
Mutational Status ◽  
Ubiquitin Ligase Complex

N6-isopentenyladenosine has been shown to exert potent in vitro antitumor activity on different human cancers, including colorectal cancer. Although some potential biochemical targets have been identified, its precise mechanism of action remains unclear. We found that N6-isopentenyladenosine affects colorectal cancer proliferation in in vitro models carrying different mutational status of FBXW7 and TP53 genes, and in HCT116 xenografts in SCID mice, by increasing the expression of the well-established tumor suppressor FBXW7, a component of the SCF-E3 ubiquitin ligase complex that promotes degradation of various oncoproteins and transcription factors, such as c-Myc, SREBP and Mcl1. Corroborating our previous studies, we identified for the first time the FBXW7/SREBP/FDPS axis as a target of the compound. Pull down of ubiquitinated proteins, immunoprecipitation and luciferase assays, reveal that through the increase of FBXW7/c-Myc binding, N6-isopentenyladenosine induces the ubiquitination of c-Myc, inhibiting its transcriptional activity. Moreover, in FBXW7- and TP53-wild type cells, N6-isopentenyladenosine strongly synergizes with 5-Fluorouracil to inhibit colon cancer growth in vitro. Our results provide novel insights into the molecular mechanism of N6-isopentenyladenosine, revealing its multi-targeting antitumor action, in vitro and in vivo. Restoring of FBXW7 tumor-suppressor represents a valid therapeutic tool, enabling N6-isopentenyladenosine as optimizable compound for patient-personalized therapies in colorectal cancer.

scholarly journals Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

2020 ◽  
Vol 52 (10) ◽  
pp. 1637-1651 ◽  
Author(s):  
Sang-Min Jang ◽  
Christophe E. Redon ◽  
Bhushan L. Thakur ◽  
Meriam K. Bahta ◽  
Mirit I. Aladjem
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

scholarly journals The role of SCF ubiquitin-ligase complex at the beginning of life

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Jiayan Xie ◽  
Yimei Jin ◽  
Guang Wang
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Cellular Proteins ◽  
Cell Cycle Regulators ◽  
Signal Transducers ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin Ligase Complex ◽  
Scf Ubiquitin Ligase

AbstractAs the largest family of E3 ligases, the Skp1-cullin 1-F-box (SCF) E3 ligase complex is comprised of Cullins, Skp1 and F-box proteins. And the SCF E3 ubiquitin ligases play an important role in regulating critical cellular processes, which promote degradation of many cellular proteins, including signal transducers, cell cycle regulators, and transcription factors. We review the biological roles of the SCF ubiquitin-ligase complex in gametogenesis, oocyte-to-embryo transition, embryo development and the regulation for estrogen and progestin. We find that researches about the SCF ubiquitin-ligase complex at the beginning of life are not comprehensive, thus more in-depth researches will promote its eventual clinical application.

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