TY  - JOUR
A1  - Hesbacher, Sonja
A1  - Pfitzer, Lisa
A1  - Wiedorfer, Katharina
A1  - Angermeyer, Sabrina
A1  - Borst, Andreas
A1  - Haferkamp, Sebastian
A1  - Scholz, Claus-Jürgen
A1  - Wobser, Marion
A1  - Schrama, David
A1  - Houben, Roland
T1  - RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells
JF  - Oncotarget
N2  - The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells.
KW  - Merkel cell carcinoma
KW  - polyomavirus
KW  - Large T antigen
KW  - retinoblastoma protein
KW  - viral carcinogenesis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177858
VL  - 7
IS  - 22
ER  - 
TY  - JOUR
A1  - Grimm, Johannes
A1  - Hufnagel, Anita
A1  - Wobser, Marion
A1  - Borst, Andreas
A1  - Haferkamp, Sebastian
A1  - Houben, Roland
A1  - Meierjohann, Svenja
T1  - BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1
JF  - Oncogenesis
N2  - 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.
KW  - melanoma
KW  - senescence
KW  - BRAF
KW  - tumor
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177261
VL  - 7
IS  - 71
ER  -