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Article ; Online: ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination.

Capecchi, Mario R / Pozner, Amir

2015 Volume 6, Page(s) 8763

Abstract: We generate a mouse model for the human microcephaly syndrome by mutating the ASPM locus, and demonstrate a premature exhaustion of the neuronal progenitor pool due to dysfunctional self-renewal processes. Earlier studies have linked ASPM mutant ... ...

Abstract	We generate a mouse model for the human microcephaly syndrome by mutating the ASPM locus, and demonstrate a premature exhaustion of the neuronal progenitor pool due to dysfunctional self-renewal processes. Earlier studies have linked ASPM mutant progenitor excessive cell cycle exit to a mitotic orientation defect. Here, we demonstrate a mitotic orientation-independent effect of ASPM on cell cycle duration. We pinpoint the cell fate-determining factor to the length of time spent in early G1 before traversing the restriction point. Characterization of the molecular mechanism reveals an interaction between ASPM and the Cdk2/Cyclin E complex, regulating the Cyclin activity by modulating its ubiquitination, phosphorylation and localization into the nucleus, before the cell is fated to transverse the restriction point. Thus, we reveal a novel function of ASPM in mediating the tightly coordinated Ubiquitin- Cyclin E- Retinoblastoma- E2F bistable-signalling pathway controlling restriction point progression and stem cell maintenance.
MeSH term(s)	Animals ; Calmodulin-Binding Proteins/genetics ; Calmodulin-Binding Proteins/metabolism ; Cell Cycle ; Cell Division ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Cyclin E/genetics ; Cyclin E/metabolism ; Cyclin-Dependent Kinase 2/genetics ; Cyclin-Dependent Kinase 2/metabolism ; E2F Transcription Factors/genetics ; E2F Transcription Factors/metabolism ; G1 Phase ; Humans ; Mice ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Phosphorylation ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Stem Cells/cytology ; Stem Cells/enzymology ; Stem Cells/metabolism ; Ubiquitination
Chemical Substances	ASPM protein, mouse ; Calmodulin-Binding Proteins ; Cyclin E ; E2F Transcription Factors ; Nerve Tissue Proteins ; Retinoblastoma Protein ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22)
Language	English
Publishing date	2015-11-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms9763
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Article ; Online: Medial Sural Artery Perforator Flap for Leg and Knee Coverage: Extended Skin Paddle With 2 Perforators.

Luca-Pozner, Vlad / Delgove, Anais / Kerfant, Nathalie / Karra, Amir / Herlin, Christian / Chaput, Benoit

Annals of plastic surgery

2020 Volume 85, Issue 6, Page(s) 650–655

Abstract: Background: For soft-tissue defect coverage in the lower leg and around the knee joint, the gastrocnemius muscle flap is the most commonly used. Having constant anatomy, a long pedicle, and decreased donor site morbidity, the medial sural artery ... ...

Abstract	Background: For soft-tissue defect coverage in the lower leg and around the knee joint, the gastrocnemius muscle flap is the most commonly used. Having constant anatomy, a long pedicle, and decreased donor site morbidity, the medial sural artery perforator (MSAP) flap may represent a good reconstructive alternative. The aim of this report was to present the experience of using a dual perforator MSAP pedicled flap. Methods: Nineteen patients underwent soft-tissue reconstruction by MSAP flap in the one third of the lower leg and around the knee joint. Eleven patients were injured in traffic accidents. Exposure of a knee prosthesis required flap coverage in 4 cases. The other defect etiologies were a gunshot wound, bone abscess due to a sickle cell anemia, bone exposure due to a full thickness burn, and sarcoma resection. Defect dimensions ranged from 7 × 5 cm to 15 × 8 cm. Seventeen flaps were harvested with 2 perforators. Donor sites were closed primary in 16 of the 19 cases. Results: The sizes of the MSAP flaps ranged from 7 to 22 cm × 5 to 8 cm. The procedure was uneventful in 17 cases. The 2 unsuccessful flaps developed a distal necrosis, for which an excision with direct suture was made secondary. Complete healing was achieved in all cases. Conclusions: The pedicled MSAP flap represents a versatile option in soft-tissue defect coverage of the lower leg and around the knee joint. Inclusion of 2 perforators could render the flap safer and increase its skin paddle, making it suitable for larger defects.
MeSH term(s)	Humans ; Knee Joint/surgery ; Leg ; Perforator Flap ; Reconstructive Surgical Procedures ; Soft Tissue Injuries/surgery ; Wounds, Gunshot
Language	English
Publishing date	2020-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	423835-7
ISSN	1536-3708 ; 0148-7043
ISSN (online)	1536-3708
ISSN	0148-7043
DOI	10.1097/SAP.0000000000002356
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Zs.A 1419: Show issues

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Article ; Online: Simultaneous Lower Body Lift and Gluteal Implants: Severe Complications Related to the Same Incisional Approach.

Luca-Pozner, Vlad / Herlin, Christian / Karra, Amir / Fluieraru, Sergiu / Boissiere, Florian / Chaput, Benoit

Plastic and reconstructive surgery

2018 Volume 142, Issue 2, Page(s) 237e–239e

MeSH term(s)	Algorithms ; Buttocks ; Humans ; Prostheses and Implants ; Weight Loss
Language	English
Publishing date	2018-05-10
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	208012-6
ISSN	1529-4242 ; 0032-1052 ; 0096-8501
ISSN (online)	1529-4242
ISSN	0032-1052 ; 0096-8501
DOI	10.1097/PRS.0000000000004557
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Uk I Zs.142: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: PAtCh-Cap: input strategy for improving analysis of ChIP-exo data sets and beyond.

Terooatea, Tommy W / Pozner, Amir / Buck-Koehntop, Bethany A

Nucleic acids research

2016 Volume 44, Issue 21, Page(s) e159

Abstract: Recently, a number of advances have been implemented into the core ChIP-seq (chromatin immunoprecipitation coupled with next-generation sequencing) methodology to streamline the process, reduce costs or improve data resolution. Several of these emerging ... ...

Abstract	Recently, a number of advances have been implemented into the core ChIP-seq (chromatin immunoprecipitation coupled with next-generation sequencing) methodology to streamline the process, reduce costs or improve data resolution. Several of these emerging ChIP-based methods perform additional chemical steps on bead-bound immunoprecipitated chromatin, posing a challenge for generating similarly treated input controls required for artifact removal during bioinformatics analyses. Here we present a versatile method for producing technique-specific input controls for ChIP-based methods that utilize additional bead-bound processing steps. This reported method, termed protein attached chromatin capture (PAtCh-Cap), relies on the non-specific capture of chromatin-bound proteins via their carboxylate groups, leaving the DNA accessible for subsequent chemical treatments in parallel with chromatin separately immunoprecipitated for the target protein. Application of this input strategy not only significantly enhanced artifact removal from ChIP-exo data, increasing confidence in peak identification and allowing for de novo motif searching, but also afforded discovery of a novel CTCF binding motif.
MeSH term(s)	Biochemistry/methods ; CCCTC-Binding Factor ; Chromatin/chemistry ; Chromatin Immunoprecipitation/methods ; Computational Biology/methods ; HeLa Cells ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Proteins/chemistry ; Proteins/genetics ; RNA Interference ; Repressor Proteins/metabolism
Chemical Substances	CCCTC-Binding Factor ; CTCF protein, human ; Chromatin ; Proteins ; Repressor Proteins
Language	English
Publishing date	2016-12-01
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkw741
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Zs.A 1067: Show issues

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Article ; Online: Cell-specific Kaiso (ZBTB33) Regulation of Cell Cycle through Cyclin D1 and Cyclin E1.

Pozner, Amir / Terooatea, Tommy W / Buck-Koehntop, Bethany A

The Journal of biological chemistry

2016 Volume 291, Issue 47, Page(s) 24538–24550

Abstract: The correlation between aberrant DNA methylation with cancer promotion and progression has prompted an interest in discerning the associated regulatory mechanisms. Kaiso (ZBTB33) is a specialized transcription factor that selectively recognizes ... ...

Abstract	The correlation between aberrant DNA methylation with cancer promotion and progression has prompted an interest in discerning the associated regulatory mechanisms. Kaiso (ZBTB33) is a specialized transcription factor that selectively recognizes methylated CpG-containing sites as well as a sequence-specific DNA target. Increasing reports link ZBTB33 overexpression and transcriptional activities with metastatic potential and poor prognosis in cancer, although there is little mechanistic insight into how cells harness ZBTB33 transcriptional capabilities to promote and progress disease. Here we report mechanistic details for how ZBTB33 mediates cell-specific cell cycle regulation. By utilizing ZBTB33 depletion and overexpression studies, it was determined that in HeLa cells ZBTB33 directly occupies the promoters of cyclin D1 and cyclin E1, inducing proliferation by promoting retinoblastoma phosphorylation and allowing for E2F transcriptional activity that accelerates G
MeSH term(s)	Cyclin D1/genetics ; Cyclin D1/metabolism ; Cyclin E/genetics ; Cyclin E/metabolism ; E2F Transcription Factors/genetics ; E2F Transcription Factors/metabolism ; G1 Phase/physiology ; HEK293 Cells ; HeLa Cells ; Humans ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Phosphorylation/physiology ; Response Elements/physiology ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Signal Transduction/physiology ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	CCND1 protein, human ; CCNE1 protein, human ; Cyclin E ; E2F Transcription Factors ; Oncogene Proteins ; Retinoblastoma Protein ; Transcription Factors ; ZBTB33 protein, human ; Cyclin D1 (136601-57-5)
Language	English
Publishing date	2016-09-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.746370
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Article ; Online: A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18-SSX Induces Canonical BAF Destruction.

Li, Jinxiu / Mulvihill, Timothy S / Li, Li / Barrott, Jared J / Nelson, Mary L / Wagner, Lena / Lock, Ian C / Pozner, Amir / Lambert, Sydney Lynn / Ozenberger, Benjamin B / Ward, Michael B / Grossmann, Allie H / Liu, Ting / Banito, Ana / Cairns, Bradley R / Jones, Kevin B

Cancer discovery

2021 Volume 11, Issue 10, Page(s) 2620–2637

Abstract: Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that ... ...

Abstract	Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that combined
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Oncogene Proteins, Fusion/genetics ; SMARCB1 Protein/genetics ; Sarcoma, Synovial/genetics ; Sarcoma, Synovial/pathology
Chemical Substances	Oncogene Proteins, Fusion ; SMARCB1 Protein ; SMARCB1 protein, human ; SS18-SSX1 fusion protein
Language	English
Publishing date	2021-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-20-1219
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Zs.A 6916: Show issues

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Article ; Online: ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

Pozner, Amir / Li, Li / Verma, Shiv Prakash / Wang, Shuxin / Barrott, Jared J / Nelson, Mary L / Yu, Jamie S E / Negri, Gian Luca / Colborne, Shane / Hughes, Christopher S / Zhu, Ju-Fen / Lambert, Sydney L / Carroll, Lara S / Smith-Fry, Kyllie / Stewart, Michael G / Kannan, Sarmishta / Jensen, Bodrie / John, Cini M / Sikdar, Saif /

Liu, Hongrui / Dang, Ngoc Ha / Bourdage, Jennifer / Li, Jinxiu / Vahrenkamp, Jeffery M / Mortenson, Katelyn L / Groundland, John S / Wustrack, Rosanna / Senger, Donna L / Zemp, Franz J / Mahoney, Douglas J / Gertz, Jason / Zhang, Xiaoyang / Lazar, Alexander J / Hirst, Martin / Morin, Gregg B / Nielsen, Torsten O / Shen, Peter S / Jones, Kevin B

Nature communications

2024 Volume 15, Issue 1, Page(s) 1165

Abstract: The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic ...

Abstract	The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.
MeSH term(s)	Animals ; Mice ; Humans ; Proteomics ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/pathology ; Translocation, Genetic ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Kidney Neoplasms/genetics ; Chromatin/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Chromosomes, Human, X/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Valosin Containing Protein/genetics
Chemical Substances	Oncogene Proteins, Fusion ; Chromatin ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; TFE3 protein, human ; ASPSCR1 protein, human ; Intracellular Signaling Peptides and Proteins ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6)
Language	English
Publishing date	2024-02-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45280-5
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Article: Intracellular calcium dynamics in cortical microglia responding to focal laser injury in the PC::G5-tdT reporter mouse.

Pozner, Amir / Xu, Ben / Palumbos, Sierra / Gee, J Michael / Tvrdik, Petr / Capecchi, Mario R

Frontiers in molecular neuroscience

2015 Volume 8, Page(s) 12

Abstract: Microglia, the resident immune cells of the brain parenchyma, are highly responsive to tissue injury. Following cell damage, microglial processes redirect their motility from randomly scouting the extracellular space to specifically reaching toward the ... ...

Abstract	Microglia, the resident immune cells of the brain parenchyma, are highly responsive to tissue injury. Following cell damage, microglial processes redirect their motility from randomly scouting the extracellular space to specifically reaching toward the compromised tissue. While the cell morphology aspects of this defense mechanism have been characterized, the intracellular events underlying these responses remain largely unknown. Specifically, the role of intracellular Ca(2+) dynamics has not been systematically investigated in acutely activated microglia due to technical difficulty. Here we used live two-photon imaging of the mouse cortex ubiquitously expressing the genetically encoded Ca(2+) indicator GCaMP5G and fluorescent marker tdTomato in central nervous system microglia. We found that spontaneous Ca(2+) transients in microglial somas and processes were generally low (only 4% of all microglia showing transients within 20 min), but baseline activity increased about 8-fold when the animals were treated with LPS 12 h before imaging. When challenged with focal laser injury, an additional surge in Ca(2+) activity was observed in the somas and protruding processes. Notably, coherent and simultaneous Ca(2+) rises in multiple microglial cells were occasionally detected in LPS-treated animals. We show that Ca(2+) transients were pre-dominantly mediated via purinergic receptors. This work demonstrates the usefulness of genetically encoded Ca(2+) indicators for investigation of microglial physiology.
Language	English
Publishing date	2015-05-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2015.00012
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Article ; Online: The C-Terminal Zinc Fingers of ZBTB38 are Novel Selective Readers of DNA Methylation.

Pozner, Amir / Hudson, Nicholas O / Trewhella, Jill / Terooatea, Tommy W / Miller, Sven A / Buck-Koehntop, Bethany A

Journal of molecular biology

2017 Volume 430, Issue 3, Page(s) 258–271

Abstract: Methyl-CpG binding proteins play an essential role in translating DNA methylation marks into a downstream transcriptional response, which has implications for both normal cell function as well as disease. Although for many of these proteins, a detailed ... ...

Abstract	Methyl-CpG binding proteins play an essential role in translating DNA methylation marks into a downstream transcriptional response, which has implications for both normal cell function as well as disease. Although for many of these proteins, a detailed mechanistic understanding for how this cellular process is mediated remains to be determined. ZBTB38 is an under-characterized member of the zinc finger (ZF) family of methyl-CpG binding proteins. Functional knowledge has been gained for its conserved methylated DNA binding N-terminal ZF region; however, a specific role for the C-terminal set of five ZFs remains to be elucidated. Here we demonstrate for the first time that a subset of the C-terminal ZBTB38 ZFs exhibit high-affinity DNA interactions and that preferential targeting of the consensus DNA site is methyl specific. Utilizing a hybrid approach, a model for the C-terminal ZBTB38 ZFs in complex with its cognate DNA target is proposed, providing insight into a possible novel mode of methylated DNA recognition. Furthermore, it is shown that the C-terminal ZFs of ZBTB38 can directly occupy promoters harboring the newly identified sequence motif in cell in a methyl-dependent manner and, depending on the gene context, contribute to modulating transcriptional response. Combined, these findings provide evidence for a key and novel physiological function for the C-terminal ZF domain of ZBTB38.
MeSH term(s)	Amino Acid Sequence ; CpG Islands ; DNA/chemistry ; DNA/metabolism ; DNA Methylation ; Humans ; Molecular Docking Simulation ; Protein Binding ; Repressor Proteins/chemistry ; Repressor Proteins/metabolism ; Zinc Fingers
Chemical Substances	Repressor Proteins ; ZBTB38 protein, human ; DNA (9007-49-2)
Language	English
Publishing date	2017-12-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2017.12.014
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Article: ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

Pozner, Amir / Verma, Shiv Prakash / Li, Li / Wang, Shuxin / Barrott, Jared J / Nelson, Mary L / Yu, Jamie S E / Negri, Gian Luca / Colborne, Shane / Hughes, Christopher S / Zhu, Ju-Fen / Lambert, Sydney L / Carroll, Lara S / Smith-Fry, Kyllie / Stewart, Michael G / Kannan, Sarmishta / Jensen, Bodrie / Mortenson, Katelyn L / John, Cini /

Sikdar, Saif / Liu, Hongrui / Dang, Ngoc Ha / Bourdage, Jennifer / Li, Jinxiu / Vahrenkamp, Jeffery M / Groundland, John S / Wustrack, Rosanna / Senger, Donna L / Zemp, Franz J / Mahoney, Douglas J / Gertz, Jason / Zhang, Xiaoyang / Lazar, Alexander J / Hirst, Martin / Morin, Gregg B / Nielsen, Torsten O / Shen, Peter S / Jones, Kevin B

bioRxiv : the preprint server for biology

2023

Abstract: The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic ... ...

Abstract	The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis
Language	English
Publishing date	2023-10-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.29.560242
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