TY  - INPR
A1  - Löffler, Mona C.
A1  - Mayer, Alexander E.
A1  - Trujillo Viera, Jonathan
A1  - Loza Valdes, Angel
A1  - El-Merahib, Rabih
A1  - Ade, Carsten P.
A1  - Karwen, Till
A1  - Schmitz, Werner
A1  - Slotta, Anja
A1  - Erk, Manuela
A1  - Janaki-Raman, Sudha
A1  - Matesanz, Nuria
A1  - Torres, Jorge L.
A1  - Marcos, Miguel
A1  - Sabio, Guadalupe
A1  - Eilers, Martin
A1  - Schulze, Almut
A1  - Sumara, Grzegorz
T1  - Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
T2  - The EMBO Journal
N2  - Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others, activates G-protein coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancerbinding protein (C/EBP)-α and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, loss of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.
KW  - AMP-activated protein kinase (AMPK)
KW  - Beige adipocytes
KW  - β3 adrenergic receptor (ADRB3)
KW  - C/EBP
KW  - Protein kinase D1 (PKD1)
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176093
ER  - 
TY  - JOUR
A1  - Meder, Lydia
A1  - König, Katharina
A1  - Ozretić, Luka
A1  - Schultheis, Anne M.
A1  - Ueckeroth, Frank
A1  - Ade, Carsten P.
A1  - Albus, Kerstin
A1  - Boehm, Diana
A1  - Rommerscheidt-Fuss, Ursula
A1  - Florin, Alexandra
A1  - Buhl, Theresa
A1  - Hartmann, Wolfgang
A1  - Wolf, Jürgen
A1  - Merkelbach-Bruse, Sabine
A1  - Eilers, Martin
A1  - Perner, Sven
A1  - Heukamp, Lukas C.
A1  - Buettner, Reinhard
T1  - NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas
JF  - International Journal of Cancer
N2  - Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.
KW  - lung cancer
KW  - small cell lung cancer
KW  - achaete-scute homolog 1
KW  - neurogenic locus notch homolog
KW  - retinoblastoma protein
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190853
VL  - 138
IS  - 4
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  -