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Published on: September 12, 2019
Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice
Monique E Verhaegen1, Doris Mangelberger1, Paul W Harms1,2
1Department of Dermatology, University of Michigan, Ann Arbor, MI 48109.
Abstract:
Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor frequently associated with clonal integration of a polyomavirus, Merkel cell polyomavirus (MCPyV), and MCC tumor cells express putative polyomavirus oncoprotein small T antigen (sTAg) and truncated large T antigen. Here, we show robust transforming activity of sTAg in vivo in a panel of transgenic mouse models. Epithelia of preterm sTAg-expressing embryos exhibited hyperplasia, impaired differentiation, increased proliferation, and apoptosis, and activation of a DNA damage response. Epithelial transformation did not require sTAg interaction with the protein phosphatase 2A protein complex, a tumor suppressor in some other polyomavirus transformation models, but was strictly dependent on a recently described sTAg domain that binds Fbxw7, the substrate-binding component of the Skp1/Cullin1/F-box protein ubiquitin ligase complex. Postnatal induction of sTAg using a Cre-inducible transgene also led to epithelial transformation with development of lesions resembling squamous cell carcinoma in situ and elevated expression of Fbxw7 target proteins. Our data establish that expression of MCPyV sTAg alone is sufficient for rapid neoplastic transformation in vivo, implicating sTAg as an oncogenic driver in MCC and perhaps other human malignancies. Moreover, the loss of transforming activity following mutation of the sTAg Fbxw7 binding domain identifies this domain as crucial for in vivo transformation.
Insights
Merkel cell polyomavirus small T antigen (sTAg) drives tumor formation in mice. This oncogenic protein is crucial for Merkel cell carcinoma development and its transforming activity depends on binding to Fbxw7.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer often linked to Merkel cell polyomavirus (MCPyV).
- MCPyV oncoproteins, including small T antigen (sTAg), are implicated in MCC pathogenesis.
- The precise role of sTAg in tumor initiation and progression requires further elucidation.
Purpose of the Study:
- To investigate the in vivo transforming activity of MCPyV sTAg.
- To determine the molecular mechanisms underlying sTAg-mediated epithelial transformation.
- To assess the oncogenic potential of sTAg in relevant preclinical models.
Main Methods:
- Generation and analysis of transgenic mouse models expressing MCPyV sTAg.
- Histological examination of embryonic and postnatal tissues for neoplastic changes.
- Investigation of sTAg interactions with cellular proteins, including protein phosphatase 2A and Fbxw7.
- Assessment of DNA damage response and proliferation markers.
Main Results:
- sTAg expression induced epithelial hyperplasia, impaired differentiation, and increased proliferation/apoptosis in embryonic epithelia.
- Transformation was independent of sTAg interaction with protein phosphatase 2A.
- Transformation was critically dependent on a specific sTAg domain binding to Fbxw7, a component of an E3 ubiquitin ligase complex.
- Postnatal sTAg induction led to lesions resembling squamous cell carcinoma in situ and elevated Fbxw7 target proteins.
Conclusions:
- MCPyV sTAg alone is sufficient to cause rapid neoplastic transformation in vivo.
- sTAg acts as a potent oncogenic driver in Merkel cell carcinoma.
- The Fbxw7 binding domain of sTAg is essential for its in vivo transforming activity, highlighting a key mechanism in MCC pathogenesis.
