@article{PaudelFusiSchmidt2021,
  author    = {Paudel, Rupesh and Fusi, Lorenza and Schmidt, Marc},
  title     = {The MEK5/ERK5 pathway in health and disease},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {14},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22147594},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261638},
  year      = {2021},
  abstract  = {The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.},
  language  = {en}
}
@article{GrimmHufnagelWobseretal.2018,
  author    = {Grimm, Johannes and Hufnagel, Anita and Wobser, Marion and Borst, Andreas and Haferkamp, Sebastian and Houben, Roland and Meierjohann, Svenja},
  title     = {BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1},
  series = {Oncogenesis},
  volume    = {7},
  journal   = {Oncogenesis},
  number    = {71},
  doi       = {10.1038/s41389-018-0082-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177261},
  year      = {2018},
  abstract  = {Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.},
  language  = {en}
}