@article{FusiPaudelMederetal.2022,
  author    = {Fusi, Lorenza and Paudel, Rupesh and Meder, Katharina and Schlosser, Andreas and Schrama, David and Goebeler, Matthias and Schmidt, Marc},
  title     = {Interaction of transcription factor FoxO3 with histone acetyltransferase complex subunit TRRAP modulates gene expression and apoptosis},
  series = {Journal of Biological Chemistry},
  volume    = {298},
  journal   = {Journal of Biological Chemistry},
  number    = {3},
  doi       = {10.1016/j.jbc.2022.101714},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299820},
  year      = {2022},
  abstract  = {Forkhead box O (FoxO) transcription factors are conserved proteins involved in the regulation of life span and age-related diseases, such as diabetes and cancer. Stress stimuli or growth factor deprivation promotes nuclear localization and activation of FoxO proteins, which—depending on the cellular context—can lead to cell cycle arrest or apoptosis. In endothelial cells (ECs), they further regulate angiogenesis and may promote inflammation and vessel destabilization implicating a role of FoxOs in vascular diseases. In several cancers, FoxOs exert a tumor-suppressive function by regulating proliferation and survival. We and others have previously shown that FoxOs can regulate these processes via two different mechanisms: by direct binding to forkhead-responsive elements at the promoter of target genes or by a poorly understood alternative process that does not require direct DNA binding and regulates key targets in primary human ECs. Here, we performed an interaction study in ECs to identify new nuclear FoxO3 interaction partners that might contribute to FoxO-dependent gene regulation. Mass spectrometry analysis of FoxO3-interacting proteins revealed transformation/transcription domain-associated protein (TRRAP), a member of multiple histone acetyltransferase complexes, as a novel binding partner of FoxO family proteins. We demonstrate that TRRAP is required to support FoxO3 transactivation and FoxO3-dependent G1 arrest and apoptosis in ECs via transcriptional activation of the cyclin-dependent kinase inhibitor p27\(^{kip1}\) and the proapoptotic B-cell lymphoma 2 family member, BIM. Moreover, FoxO-TRRAP interaction could explain FoxO-induced alternative gene regulation via TRRAP-dependent recruitment to target promoters lacking forkhead-responsive element sequences.},
  language  = {en}
}
@article{MederKoenigOzretićetal.2016,
  author    = {Meder, Lydia and K{\"o}nig, Katharina and Ozretić, Luka and Schultheis, Anne M. and Ueckeroth, Frank and Ade, Carsten P. and Albus, Kerstin and Boehm, Diana and Rommerscheidt-Fuss, Ursula and Florin, Alexandra and Buhl, Theresa and Hartmann, Wolfgang and Wolf, J{\"u}rgen and Merkelbach-Bruse, Sabine and Eilers, Martin and Perner, Sven and Heukamp, Lukas C. and Buettner, Reinhard},
  title     = {NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas},
  series = {International Journal of Cancer},
  volume    = {138},
  journal   = {International Journal of Cancer},
  number    = {4},
  doi       = {10.1002/ijc.29835},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190853},
  pages     = {927-938},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}