Joël P. Charles

Philipps University of Marburg

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Thorsten Stiewe

German Center for Lung Research

Michael Wanzel

Philipps University of Marburg

Andrea Nist

Philipps University of Marburg

Anne Catherine Bretz

German Center for Lung Research

Jonas B. Vischedyk

Goethe University Frankfurt

Marco Mernberger

Philipps University of Marburg

Fotini Vogiatzi

University Hospital Schleswig-Holstein

Mirjam Hefter

Philipps University of Marburg

Niklas Gremke

Philipps University of Marburg

Oleg Timofeev

German Center for Lung Research

Cooperative Institutions

Philipps University of Marburg

Universitätsklinikum Gießen und Marburg

University of Giessen

Heidelberg University

German Center for Lung Research

University of Würzburg

Universities of Giessen and Marburg Lung Center

Goethe University Frankfurt

Institute of Molecular Biology

German Cancer Research Center

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Monitoring the dynamics of clonal tumor evolution in vivo using secreted luciferases

European Journal of Cancer (2016)

Joël P. Charles Jean Fuchs Mirjam Hefter Jonas B. Vischedyk Maximilian Kleint

Luciferases

Dynamics

10.1016/s0959-8049(16)61244-3

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Citations (0)

CRISPR-Cas9-based target validation for p53-reactivating model compounds

European Journal of Cancer (2016)

Michael Wanzel Jonas B. Vischedyk Miriam P. Gittler Niklas Gremke Marco Mernberger

10.1016/s0959-8049(16)61433-8

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Citations (3)

ΔNp63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma

Nucleic Acids Research (2016)

Anne Catherine Bretz Miriam P. Gittler Joël P. Charles Niklas Gremke I Eckhardt

TP63, a member of the p53 gene family gene, encodes the ΔNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC). Using an epiallelic series of siRNAs with intrinsically different knockdown abilities, we show that the complete loss of ΔNp63 strongly impaired cell proliferation, whereas partial ΔNp63 depletion rendered cells hypersensitive to cisplatin accompanied by an accumulation of DNA damage. Expression profiling revealed wide-spread transcriptional regulation of DNA repair genes and in particular Fanconi anemia (FA) pathway components such as FANCD2 and RAD18 - known to be crucial for the repair of cisplatin-induced interstrand crosslinks. In SCC patients ΔNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming ΔNp63 as a key activator of the FA pathway in vivo Mechanistically, ΔNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by ΔNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of ΔNp63. Together, our results demonstrate that ΔNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting ΔNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy.

FANCD2

10.1093/nar/gkw036

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Citations (23)

CRISPR-Cas9–based target validation for p53-reactivating model compounds

Nature Chemical Biology (2015)

Michael Wanzel Jonas B. Vischedyk Miriam P. Gittler Niklas Gremke Julia R. Seiz

10.1038/nchembio.1965

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Citations (79)

Life or death

Cell Cycle (2010)

Katharina Schlereth Joël P. Charles Anne Catherine Bretz Thorsten Stiewe

The tumor suppressor p53 provides exquisite protection from cancer by balancing cell survival and death in response to stress. Sustained stress or irreparable damage trigger p53's killer functions to permanently eliminate genetically-altered cells as a potential source of cancer. To prevent the unnecessary loss of cells that could cause premature aging as a result of stem cell attrition, the killer functions of p53 are tightly regulated and balanced against protector functions that promote damage repair and support survival in response to low stress or mild damage. In molecular terms these p53-based cell fate decisions involve protein interactions with cofactors and modifying enzymes, which modulate the activation of distinct sets of p53 target genes. In addition, we demonstrate that part of this regulation occurs at the level of DNA binding. We show that the killer function of p53 requires the four DNA binding domains within the p53 tetramer to interact with one another. These intermolecular interactions enable cooperative binding of p53 to less perfect response elements in the genome, which are present in many target genes essential for apoptosis. Modulating p53 interactions within the tetramer could therefore present a novel promising strategy to fine-tune p53-based cell fate decisions.

Cell fate determination

10.4161/cc.9.20.13595

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Citations (52)

DNA Binding Cooperativity of p53 Modulates the Decision between Cell-Cycle Arrest and Apoptosis

Molecular Cell (2010)

Katharina Schlereth Rasa Beinoravičiūtė-Kellner Markus Zeitlinger Anne Catherine Bretz Markus Sauer

Cooperativity

Cooperative binding

10.1016/j.molcel.2010.02.037

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Citations (104)

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Proceedings of the National Academy of Sciences (2016)

Fotini Vogiatzi Dominique T. Brandt Jean Schneikert Jeannette Fuchs Katharina Grikscheit

Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.

Tumor progression

10.1073/pnas.1612711114

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Citations (86)

NFATc1 as a therapeutic target in FLT3-ITD-positive AML

Leukemia (2015)

Stephan Metzelder Christian Michel Malte von Bonin Miriam Rehberger Elisabeth Heßmann

NFAT

Hematology

10.1038/leu.2015.95

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Citations (47)

Monitoring the dynamics of clonal tumour evolution in vivo using secreted luciferases

Nature Communications (2014)

Joël P. Charles Jeannette Fuchs Mirjam Hefter Jonas B. Vischedyk Maximilian Kleint

Tumours are heterogeneous cell populations that undergo clonal evolution during tumour progression, metastasis and response to therapy. Short hairpin RNAs (shRNAs) generate stable loss-of-function phenotypes and are versatile experimental tools to explore the contribution of individual genetic alterations to clonal evolution. In these experiments tumour cells carrying shRNAs are commonly tracked with fluorescent reporters. While this works well for cell culture studies and leukaemia mouse models, fluorescent reporters are poorly suited for animals with solid tumours--the most common tumour types in cancer patients. Here we develop a toolkit that uses secreted luciferases to track the fate of two different shRNA-expressing tumour cell clones competitively, both in vitro and in vivo. We demonstrate that secreted luciferase activities can be measured robustly in the blood stream of tumour-bearing mice to accurately quantify, in a minimally invasive manner, the dynamic evolution of two genetically distinct tumour subclones in preclinical mouse models of tumour development, metastasis and therapy.

Tumour heterogeneity

10.1038/ncomms4981

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Citations (23)