Schrama, David and Hesbacher, Sonja and Angermeyer, Sabrina and Schlosser, Andreas and Haferkamp, Sebastian and Aue, Annemarie and Adam, Christian and Weber, Alexandra and Schmidt, Marc and Houben, Roland (2016) Serine 220 phosphorylation of the Merkel cell polyomavirus large T antigen crucially supports growth of Merkel cell carcinoma cells. INTERNATIONAL JOURNAL OF CANCER, 138 (5). pp. 1153-1162. ISSN 0020-7136, 1097-0215
Full text not available from this repository. (Request a copy)Abstract
Merkel cell polyomavirus (MCPyV) is regarded as a major causal factor for Merkel cell carcinoma (MCC). Indeed, tumor cell growth of MCPyV-positive MCC cells is dependent on the expression of a truncated viral Large T antigen (LT) with an intact retinoblastoma protein (RB)-binding site. Here we determined the phosphorylation pattern of a truncated MCPyV-LT characteristically for MCC by mass spectrometry revealing MCPyV-LT as multi-phospho-protein phosphorylated at several serine and threonine residues. Remarkably, disruption of most of these phosphorylation sites did not affect its ability to rescue knockdown of endogenous T antigens in MCC cells indicating that phosphorylation of the respective amino acids is not essential for the growth promoting function of MCPyV-LT. However, alteration of serine 220 to alanine completely abolished the ability of MCPyV-LT to support proliferation of MCC cells. Conversely, mimicking the phosphorylated state by mutation of serine 220 to glutamic acid resulted in a fully functional LT. Moreover, MCPyV-LT S220A demonstrated reduced binding to RB in co-immunoprecipitation experiments as well as weaker induction of RB target genes in MCC cells. In conclusion, we provide evidence that phosphorylation of serine 220 is required for efficient RB inactivation in MCC and may therefore be a potential target for future therapeutic approaches.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RETINOBLASTOMA TUMOR-SUPPRESSOR; NUCLEAR-LOCALIZATION-SIGNAL; KINASE-II PHOSPHORYLATION; HUMAN-PAPILLOMAVIRUS E7; PROTEIN FUNCTION; MECHANISMS; CANCER; SIMIAN-VIRUS-40; DOMAINS; UPDATE; merkel cell carcinoma; polyomavirus; Large T antigen; phosphorylation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 Mar 2019 14:43 |
| Last Modified: | 11 Mar 2019 14:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2377 |
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