BK virus large T antigen: interactions with the retinoblastoma family of tumor suppressor proteins and effects on cellular growth control

Abstract

BK virus (BKV) is a polyomavirus which infects a large percentage of the human population. It is a potent transforming agent and is tumorigenic in rodents. BKV DNA has also been found in human brain, pancreatic islet, and urinary tract tumors, implicating this virus in neoplastic processes. BKV T antigen (TAg) is highly homologous to simian virus 40 TAg, particularly in regions required for mitogenic stimulation and binding to tumor suppressor proteins. The experiments presented in this report show that BKV TAg can bind the tumor suppressor protein p53. BKV TAg also has the ability to bind to members of the retinoblastoma (pRb) family of tumor suppressor proteins both in vivo and in vitro. However, these interactions are detected only when large amounts of total protein are used, because the levels of BKV TAg normally produced from viral promoterenhancer elements are too low to bind a significant amount of the pRb family proteins in the cell. The low levels of BKV TAg produced by the viral promoter elements are sufficient to affect the levels and the phosphorylation patterns of these proteins and to induce serum-independent growth in these cells. Additional events, however, are required for full transformation. These data further support the notion that BKV TAg can affect cellular growth control mechanisms and may in fact be involved in neoplastic processes.

Cidofovir Inhibits Polyomavirus BK Replication in Human Renal Tubular Cells Downstream of Viral Early Gene Expression

“…This effect was more pronounced in BKV‐infected than in uninfected RPTECs. Interestingly, both, DNA replication and metabolic activity was increased following BKV infection which is a consequence of large T‐antigen inactivating the tumor‐suppressor proteins Rb and p53 and stimulating cell progression into S‐phase (32). Thus, CDV at 40 μg/mL decreased BrdU and WST‐1 activities to levels seen in uninfected untreated cells.…”

BK Virus Associated Renal Cell Carcinoma: Case Presentation with Optimized PCR and Other Diagnostic Tests

“…BKV TAg binds and inactivates regulators of cell cycle control including the pRB family of proteins and p53 tumor suppressor gene products (15). Binding of p53 by TAg stabilizes wild‐type p53 and functionally inhibits the p53‐mediated response to DNA damage (16–17). Expression of TAg immortalizes human cells in culture, transforms rodent cells in culture and induces tumors in transgenic mice.…”

Episomal vectors for gene expression in mammalian cells

“…In particular, the large T antigen of the Polyomavirinae is known to have a broad interaction range, which has limited the exploration of BKV vectors as an efficient tool for gene therapy. At physiological levels, BKV T antigen is able to bind most of p53 in the cell [179]. p53 is important in cell cycle arrest and apoptosis, which means that loss of p53 function is a major cause (50%) of transformation.…”