RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells.
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.
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Sonja
S
Hesbacher
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.|Department of Pharmacy, Center for Drug Research, University of Munich (Ludwigs-Maximilians-Universität), Munich, Germany.
Lisa
L
Pfitzer
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Katharina
K
Wiedorfer
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Sabrina
S
Angermeyer
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Andreas
A
Borst
Department of Dermatology, University of Regensburg, Regensburg, Germany.
Sebastian
S
Haferkamp
Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany.
Claus-Jürgen
CJ
Scholz
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Marion
M
Wobser
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
David
D
Schrama
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Roland
R
Houben
D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D059965:Merkel cell polyomavirus / Q000378:metabolism; D027601:Polyomavirus Infections / Q000235:genetics / Q000378:metabolism; D056286:Retinoblastoma Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases
Large T antigen; Merkel cell carcinoma; polyomavirus; retinoblastoma protein; viral carcinogenesis