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Skin Lymphoma Cancer Cell

Unique Nuclear Role of MCPyV Small Tumor Antigen in MCC

June, 06, 2024 | Skin Cancer

KEY TAKEAWAYS

  • The study aimed to investigate the unique nuclear localization mechanism of the MCPyV small tumor antigen in MCC.
  • Researchers noticed that MCPyV ST’s unique nuclear localization distinguishes it from other polyomavirus ST proteins, highlighting its role in MCC oncogenesis.

Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that is 3 times deadlier than melanoma. In 2008, it was found that 80% of MCC cases are caused by the genomic integration of a novel polyomavirus, Merkel Cell Polyomavirus (MCPyV), and the expression of its small and truncated large tumor antigens (ST and LT-t, respectively). MCPyV belongs to a family of human polyomaviruses; however, it is the only one with a clear association with cancer.

Kaira R Thevenin and the team aimed to assess the unique nuclear localization mechanism of the MCPyV small tumor antigen in MCC.

They performed an inclusive analysis to investigate the role and mechanisms of various polyomavirus tumor antigens in cellular transformation. Rat-2 and 293A cells were transduced with pLENTI constructs encoding MCPyV LT-t, MCPyV ST, TSPyV ST, HPyV7 ST, or an empty pLENTI vector. These cells were then assessed through multiple transformation assays and subcellular fractionations to determine the effects of these antigens on cellular behavior. Statistical significance was evaluated using one-way ANOVA tests.

The soft agar, proliferation, doubling time, glucose uptake, and serum dependence assays confirmed ST to be the dominant transforming protein of MCPyV. Furthermore, it was found that MCPyV ST is uniquely transforming, as the ST antigens of other non-oncogenic human polyomaviruses, such as Trichodysplasia Spinulosa-Associated Polyomavirus (TSPyV) and Human Polyomavirus 7 (HPyV7), were not transforming when similarly assessed. Identification of structural dissimilarities between transforming and non-transforming tumor antigens revealed that the uniquely transforming domain(s) of MCPyV ST is likely located within the structurally dissimilar loops of the MCPyV ST unique region.

Of all known MCPyV ST cellular interactors, 62% are exclusively or transiently nuclear, suggesting that MCPyV ST localizes to the nucleus despite the absence of a canonical nuclear localization signal. Indeed, subcellular fractionations confirmed that MCPyV ST could achieve nuclear localization through a currently unknown, regulated mechanism independent of its small size, as HPyV7 and TSPyV ST proteins were incapable of nuclear translocation.

Although nuclear localization was found to be important for several transforming properties of MCPyV ST, some properties were also performed by a cytoplasmic sequestered MCPyV ST, suggesting that MCPyV ST may perform different transforming functions in individual subcellular compartments.

The study concluded that these data further elucidate the unique differences between MCPyV ST and other polyomavirus ST proteins, providing essential insights to understand MCPyV as the only known human oncogenic polyomavirus.

The study received funding from the Stetson University Health Sciences Department and Cell Biology Education Consortium.

Source: https://pubmed.ncbi.nlm.nih.gov/38831469/

Thevenin KR, Tieche IS, Di Benedetto CE, et al.(2024). “The small tumor antigen of Merkel cell polyomavirus accomplishes cellular transformation by uniquely localizing to the nucleus despite the absence of a known nuclear localization signal.” Virol J. 2024 Jun 3;21(1):125. doi: 10.1186/s12985-024-02395-x. PMID: 38831469.

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