LIVIVO - Search results -

Search results

Result 1 - 10 of total 11

Search options

Article ; Online: Mdm2 as a chromatin modifier.

Wienken, Magdalena / Moll, Ute M / Dobbelstein, Matthias

2017 Volume 9, Issue 1, Page(s) 74–80

Abstract: Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb ...

Abstract	Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb group (PcG) family. PcG proteins form polycomb repressive complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27) trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119) monoubiquitination. Both PRCs mostly support a compact and transcriptionally silent chromatin structure. We found that Mdm2 regulates a gene expression profile similar to that of PRC2 independent of p53. Moreover, Mdm2 promotes the stemness of murine induced pluripotent stem cells and human mesenchymal stem cells, and supports the survival of tumour cells. Mdm2 is recruited to target gene promoters by the PRC2 member and histone methyltransferase EZH2, and enhances PRC-dependent repressive chromatin modifications, specifically H3K27me3 and H2AK119ub1. Mdm2 also cooperates in gene repression with the PRC1 protein RING1B, a H2AK119 ubiquitin ligase. Here we discuss the possible implications of these p53-independent functions of Mdm2 in chromatin dynamics and in the stem cell phenotype. We propose that the p53-independent functions of Mdm2 should be taken into account for cancer drug design. So far, the majority of clinically tested Mdm2 inhibitors target its binding to p53 but do not affect the new functions of Mdm2 described here. However, when targeting the E3 ligase activity of Mdm2, a broader spectrum of its oncogenic activities might become druggable.
MeSH term(s)	Animals ; Biological Evolution ; Chromatin/metabolism ; Genomic Instability ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Chromatin ; Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2017-02-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2500949-7
ISSN	1759-4685 ; 1674-2788
ISSN (online)	1759-4685
ISSN	1674-2788
DOI	10.1093/jmcb/mjw046
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Article ; Online: IL-1

Schmidt, Karsten / Wienken, Magdalena / Keller, Christian W / Balcarek, Peter / Münz, Christian / Schmidt, Jens

Mediators of inflammation

2017 Volume 2017, Page(s) 5470831

Abstract: The pathology of inclusion body myositis (IBM) involves an inflammatory response ... ...

Abstract	The pathology of inclusion body myositis (IBM) involves an inflammatory response and
MeSH term(s)	Amyloid/metabolism ; Autophagosomes/drug effects ; Autophagy/drug effects ; Blotting, Western ; Cell Line ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Immunohistochemistry ; Interferon-gamma/pharmacology ; Interleukin-1beta/pharmacology ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Myoblasts/drug effects ; Myoblasts/metabolism ; Phosphorylation/drug effects
Chemical Substances	Amyloid ; Interleukin-1beta ; Interferon-gamma (82115-62-6) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ZDB-ID	1137605-3
ISSN	1466-1861 ; 0962-9351
ISSN (online)	1466-1861
ISSN	0962-9351
DOI	10.1155/2017/5470831
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3575: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity.

Sriraman, Anusha / Radovanovic, Marija / Wienken, Magdalena / Najafova, Zeynab / Li, Yizhu / Dobbelstein, Matthias

Oncotarget

2016 Volume 7, Issue 22, Page(s) 31623–31638

Abstract: Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these ... ...

Abstract	Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.
MeSH term(s)	Acetylation ; Aminopyridines/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Dipeptides/pharmacology ; Dose-Response Relationship, Drug ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression Regulation, Neoplastic ; HCT116 Cells ; Humans ; Imidazoles/pharmacology ; MCF-7 Cells ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/genetics ; Neoplasms/pathology ; Phosphorylation ; Piperazines/pharmacology ; Protein Phosphatase 2C/antagonists & inhibitors ; Protein Phosphatase 2C/genetics ; Protein Phosphatase 2C/metabolism ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/metabolism ; RNA Interference ; Signal Transduction/drug effects ; Time Factors ; Transcriptome ; Transfection ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation
Chemical Substances	Aminopyridines ; Dipeptides ; Enzyme Inhibitors ; GSK2830371 ; Imidazoles ; Piperazines ; TP53 protein, human ; Tumor Suppressor Protein p53 ; nutlin 3 (53IA0V845C) ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; PPM1D protein, human (EC 3.1.3.16) ; Protein Phosphatase 2C (EC 3.1.3.16)
Language	English
Publishing date	2016-05-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.9302
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Book ; Online ; Thesis: A regulatory network of Mdm2 and members of the Polycomb Group (PcG) family

Wienken, Maria Magdalena [Verfasser] / Dobbelstein, Matthias [Akademischer Betreuer] / Halyna, Shcherbata [Akademischer Betreuer] / Zeisberg, Michael [Akademischer Betreuer]

2016

Author's details	Maria Magdalena Wienken. Betreuer: Matthias Dobbelstein. Gutachter: Shcherbata Halyna ; Michael Zeisberg
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Niedersächsische Staats- und Universitätsbibliothek Göttingen
Publishing place	Göttingen
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

Full text online

Full text

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: p53 Activity Results in DNA Replication Fork Processivity.

Klusmann, Ina / Rodewald, Sabrina / Müller, Leonie / Friedrich, Mascha / Wienken, Magdalena / Li, Yizhu / Schulz-Heddergott, Ramona / Dobbelstein, Matthias

Cell reports

2016 Volume 17, Issue 7, Page(s) 1845–1857

Abstract: p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. We report that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces ... ...

Abstract	p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. We report that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces fork progression. This is observed in tumor-derived U2OS cells but also in murine embryonic fibroblasts with heterozygous or homozygous p53 deletion and in freshly isolated thymocytes from mice with differential p53 status. Mdm2, a p53-inducible gene product, similarly supports DNA replication even in p53-deficient cells, suggesting that sustained Mdm2-expression is at least one of the mechanisms allowing p53 to prevent replicative stress. Thus, p53 helps to protect the genome during S phase, by preventing the occurrence of stalled or collapsed replication forks. These results expand p53's tumor-suppressive functions, adding to the ex-post model (elimination of damaged cells) an ex-ante activity; i.e., the prevention of DNA damage during replication.
Language	English
Publishing date	2016-11-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2016.10.036
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Transcription factor TAp73 and microRNA-449 complement each other to support multiciliogenesis.

Wildung, Merit / Esser, Tilman Uli / Grausam, Katie Baker / Wiedwald, Cornelia / Volceanov-Hahn, Larisa / Riedel, Dietmar / Beuermann, Sabine / Li, Li / Zylla, Jessica / Guenther, Ann-Kathrin / Wienken, Magdalena / Ercetin, Evrim / Han, Zhiyuan / Bremmer, Felix / Shomroni, Orr / Andreas, Stefan / Zhao, Haotian / Lizé, Muriel

Cell death and differentiation

2019 Volume 26, Issue 12, Page(s) 2740–2757

Abstract: Motile cilia serve vital functions in development, homeostasis, and regeneration. We recently demonstrated that TAp73 is an essential transcriptional regulator of respiratory multiciliogenesis. Here, we show that TAp73 is expressed in multiciliated cells ...

Abstract	Motile cilia serve vital functions in development, homeostasis, and regeneration. We recently demonstrated that TAp73 is an essential transcriptional regulator of respiratory multiciliogenesis. Here, we show that TAp73 is expressed in multiciliated cells (MCCs) of diverse tissues. Analysis of TAp73 mutant animals revealed that TAp73 regulates Foxj1, Rfx2, Rfx3, axonemal dyneins Dnali1 and Dnai1, plays a pivotal role in the generation of MCCs in male and female reproductive ducts, and contributes to fertility. However, the function of MCCs in the brain appears to be preserved despite the loss of TAp73, and robust activity of cilia-related networks is maintained in the absence of TAp73. Notably, TAp73 loss leads to distinct changes in ciliogenic microRNAs: miR34bc expression is reduced, whereas the miR449 cluster is induced in diverse multiciliated epithelia. Among different MCCs, choroid plexus (CP) epithelial cells in the brain display prominent miR449 expression, whereas brain ventricles exhibit significant increase in miR449 levels along with an increase in the activity of ciliogenic E2F4/MCIDAS circuit in TAp73 mutant animals. Conversely, E2F4 induces robust transcriptional response from miR449 genomic regions. To address whether increased miR449 levels in the brain maintain the multiciliogenesis program in the absence of TAp73, we deleted both TAp73 and miR449 in mice. Although loss of miR449 alone led to a mild ciliary defect in the CP, more pronounced ciliary defects and hydrocephalus were observed in the brain lacking both TAp73 and miR449. In contrast, miR449 loss in other MCCs failed to enhance ciliary defects associated with TAp73 loss. Together, our study shows that, in addition to the airways, TAp73 is essential for generation of MCCs in male and female reproductive ducts, whereas miR449 and TAp73 complement each other to support multiciliogenesis and CP development in the brain.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Cells, Cultured ; Cilia/metabolism ; Cilia/physiology ; Humans ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Nuclear Proteins/genetics ; Tumor Protein p73/genetics ; Tumor Protein p73/metabolism
Chemical Substances	MIRN449 microRNA, human ; MicroRNAs ; Mirn449 microRNA, mouse ; Nuclear Proteins ; Tumor Protein p73 ; delta Np73, mouse
Language	English
Publishing date	2019-05-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-019-0332-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 80: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: p53 Activity Results in DNA Replication Fork Processivity

Ina Klusmann / Sabrina Rodewald / Leonie Müller / Mascha Friedrich / Magdalena Wienken / Yizhu Li / Ramona Schulz-Heddergott / Matthias Dobbelstein

Cell Reports, Vol 17, Iss 7, Pp 1845-

2016 Volume 1857

Abstract	p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. We report that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces fork progression. This is observed in tumor-derived U2OS cells but also in murine embryonic fibroblasts with heterozygous or homozygous p53 deletion and in freshly isolated thymocytes from mice with differential p53 status. Mdm2, a p53-inducible gene product, similarly supports DNA replication even in p53-deficient cells, suggesting that sustained Mdm2-expression is at least one of the mechanisms allowing p53 to prevent replicative stress. Thus, p53 helps to protect the genome during S phase, by preventing the occurrence of stalled or collapsed replication forks. These results expand p53’s tumor-suppressive functions, adding to the ex-post model (elimination of damaged cells) an ex-ante activity; i.e., the prevention of DNA damage during replication.
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2016-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

Full text online

Full text

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article: MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53

Wienken, Magdalena / Dickmanns, Antje / Nemajerova, Alice / Kramer, Daniela / Najafova, Zeynab / Weiss, Miriam / Karpiuk, Oleksandra / Kassem, Moustapha / Zhang, Yanping / Lozano, Guillermina / Johnsen, Steven A / Moll, Ute M / Zhang, Xin / Dobbelstein, Matthias

Molecular cell. 2016 Jan. 07, v. 61, no. 1

2016

Abstract: The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the ...

Abstract	The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53.
Keywords	cell proliferation ; chromatin ; fibroblasts ; genes ; histones ; humans ; induced pluripotent stem cells ; lysine ; mice ; neoplasm cells ; neoplasms ; oncogene proteins ; ubiquitin-protein ligase ; ubiquitination
Language	English
Dates of publication	2016-0107
Size	p. 68-83.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2015.12.008
Database	NAL-Catalogue (AGRICOLA)

In stock of ZB MED Bonn / Germany

Z 2005/501: Show issues

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53.

Molecular cell

2015 Volume 61, Issue 1, Page(s) 68–83

Abstract	The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Cell Survival ; Chromatin Assembly and Disassembly ; Gene Expression Regulation, Neoplastic ; HCT116 Cells ; Histones/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; MCF-7 Cells ; Mesenchymal Stem Cells/metabolism ; Methylation ; Mice ; Neoplastic Stem Cells/metabolism ; Osteogenesis ; Phenotype ; Polycomb Repressive Complex 1/metabolism ; Polycomb Repressive Complex 2/genetics ; Polycomb Repressive Complex 2/metabolism ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; RNA Interference ; Signal Transduction ; Time Factors ; Transfection ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Histones ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; MDM2 protein, human (EC 2.3.2.27) ; Mdm2 protein, mouse (EC 2.3.2.27) ; Polycomb Repressive Complex 1 (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; RNF2 protein, human (EC 2.3.2.27) ; Rnf2 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2015-12-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2015.12.008
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5055: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: TAp73 is a central transcriptional regulator of airway multiciliogenesis.

Nemajerova, Alice / Kramer, Daniela / Siller, Saul S / Herr, Christian / Shomroni, Orr / Pena, Tonatiuh / Gallinas Suazo, Cristina / Glaser, Katharina / Wildung, Merit / Steffen, Henrik / Sriraman, Anusha / Oberle, Fabian / Wienken, Magdalena / Hennion, Magali / Vidal, Ramon / Royen, Bettina / Alevra, Mihai / Schild, Detlev / Bals, Robert /

Dönitz, Jürgen / Riedel, Dietmar / Bonn, Stefan / Takemaru, Ken-Ichi / Moll, Ute M / Lizé, Muriel

Genes & development

2016 Volume 30, Issue 11, Page(s) 1300–1312

Abstract: Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs ... ...

Abstract	Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs multiciliogenesis remains poorly understood. Here we identify TP73, a p53 homolog, as governing the program for airway multiciliogenesis. Mice with TP73 deficiency suffer from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance. Organotypic airway cultures pinpoint TAp73 as necessary and sufficient for basal body docking, axonemal extension, and motility during the differentiation of MCC progenitors. Mechanistically, cross-species genomic analyses and complete ciliary rescue of knockout MCCs identify TAp73 as the conserved central transcriptional integrator of multiciliogenesis. TAp73 directly activates the key regulators FoxJ1, Rfx2, Rfx3, and miR34bc plus nearly 50 structural and functional ciliary genes, some of which are associated with human ciliopathies. Our results position TAp73 as a novel central regulator of MCC differentiation.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cells, Cultured ; Cilia/genetics ; Gene Expression Regulation/genetics ; Gene Knockout Techniques ; Mice ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Respiratory Mucosa/cytology ; Respiratory Tract Infections/genetics ; Respiratory Tract Infections/physiopathology
Chemical Substances	Nuclear Proteins ; delta Np73, mouse
Language	English
Publishing date	2016-06-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.279836.116
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 2292: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 54: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

To top

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Bonn / Germany

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito