TY  - JOUR
A1  - Schülein-Völk, Christina
A1  - Wolf, Elmar
A1  - Zhu, Jing
A1  - Xu, Wenshan
A1  - Taranets, Lyudmyla
A1  - Hellmann, Andreas
A1  - Jänicke, Laura A.
A1  - Diefenbacher, Markus E.
A1  - Behrens, Axel
A1  - Eilers, Martin
A1  - Popov, Nikita
T1  - Dual Regulation of Fbw7 Function and Oncogenic Transformation by Usp28
JF  - CELL REPORTS
N2  - Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates the turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-dependent substrate ubiquitination is antagonized by the Usp28 deubiquitinase. Here, we show that Usp28 preferentially antagonizes autocatalytic ubiquitination and stabilizes Fbw7, resulting in dose-dependent effects in Usp28 knockout mice. Monoallelic deletion of Usp28 maintains stable Fbw7 but drives Fbw7 substrate degradation. In contrast, complete knockout triggers Fbw7 degradation and leads to the accumulation of Fbw7 substrates in several tissues and embryonic fibroblasts. On the other hand, overexpression of Usp28 stabilizes both Fbw7 and its substrates. Consequently, both complete loss and ectopic expression of Usp28 promote Ras-driven oncogenic transformation. We propose that dual regulation of Fbw7 activity by Usp28 is a safeguard mechanism for maintaining physiological levels of proto-oncogenic Fbw7 substrates, which is equivalently disrupted by loss or overexpression of Usp28.
KW  - Fbw7
KW  - oncogenic transformation
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118219
SN  - 2211-1247
N1  - The sequencing data have been submitted to the GEO repository under accession number GSE59354.
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Otto, Christoph
A1  - Kastner, Carolin
A1  - Schmidt, Stefanie
A1  - Uttinger, Konstantin
A1  - Baluapuri, Apoorva
A1  - Denk, Sarah
A1  - Rosenfeldt, Mathias T.
A1  - Rosenwald, Andreas
A1  - Roehrig, Florian
A1  - Ade, Carsten P.
A1  - Schuelein-Voelk, Christina
A1  - Diefenbacher, Markus E.
A1  - Germer, Christoph-Thomas
A1  - Wolf, Elmar
A1  - Eilers, Martin
A1  - Wiegering, Armin
T1  - RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells
JF  - Molecular Oncology
N2  - Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.
KW  - CRC
KW  - CX5461
KW  - MIZ1
KW  - MYC
KW  - ribosome
KW  - RNAPOL1
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312806
VL  - 16
IS  - 15
ER  - 
TY  - JOUR
A1  - Prieto‐Garcia, Cristian
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Braun, Fabian
A1  - Fischer, Thomas
A1  - Walz, Susanne
A1  - Schülein‐Völk, Christina
A1  - Eilers, Ursula
A1  - Ade, Carsten P.
A1  - Calzado, Marco A.
A1  - Orian, Amir
A1  - Maric, Hans M.
A1  - Münch, Christian
A1  - Rosenfeldt, Mathias
A1  - Eilers, Martin
A1  - Diefenbacher, Markus E.
T1  - Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells
JF  - EMBO Molecular Medicine
N2  - The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
KW  - ∆Np63
KW  - NOTCH
KW  - squamous cell carcinoma
KW  - 28
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218303
VL  - 12
IS  - 4
ER  -