Lessons from polyoma middle T antigen on signaling and transformation: A DNA tumor virus contribution to the war on cancer

Abstract

Middle T antigen (MT) is the principal oncogene of murine polyomavirus. Its study has led to the discovery of the roles tyrosine kinase and phosphoinositide 3-kinase (PI3K) signaling in mammalian growth control and transformation. MT is necessary for viral transformation in tissue culture cells and tumorigenesis in animals. When expressed alone as a transgene, MT causes tumors in a wide variety of tissues. It has no known catalytic activity, but rather acts by assembling cellular signal transduction molecules. Protein phosphatase 2A, protein tyrosine kinase of the src family, PI3K, phospholipaseCγ1 and well as the Shc/Grb2 adaptors are all assembled on MT. Their activation set off a series of signaling cascades. Analysis of virus mutants as well as transgenic animals has demonstrated that the effects of a given signal depend not only tissue type, but on the genetic background of the host animal. There remain many opportunities as we seek a full molecular understanding of MT and apply some of its lessons to human cancer.

The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

“…One widely used transgenic mouse model of mammary tumor formation is driven by expression of MT transcribed from the MMTV promoter (Guy et al 1992). MT is a surrogate for an activated RTK and is dependent on both the PI3K and Ras/Raf pathways for transformation (Whitman et al 1985;Ichaso and Dilworth 2001;Schaffhausen and Roberts 2009). By examining the effect of heterozygous ablation of p110a on MT-induced tumorigenesis, we found that the onset of palpable tumor formation was markedly delayed upon loss of one copy of p110a ( Fig.…”

“…To study the effect of ablating p110 isoforms on MT-or NeuT-associated PI3K activity, cells were starved to minimize confounding signals from the activation of other receptors. While MT binds to the p85/p110 complex directly (Schaffhausen and Roberts 2009), HER3 recruits PI3K to an activated HER2/ Neu (Supplemental Fig. 4A).…”

“…In response to growth factor stimulation and the subsequent activation of receptor tyrosine kinases (RTKs), PI3K is recruited to the membrane via interaction of its p85 subunit with tyrosine phosphate motifs on activated receptors or to adaptor proteins associated with the receptors; e.g., insulin receptor substrate 1 (IRS1). Other receptors such as G protein-coupled receptors (GPCRs), as well as oncogenes including Ras and polyoma middle T antigen (MT), can also activate the p110 subunit (Liu et al 2009;Schaffhausen and Roberts 2009;Vanhaesebroeck et al 2010). The activated p110 catalytic subunit of PI3K then catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to form PIP 3 , which elicits multiple downstream signaling pathways.…”

Mammary epithelial-specific disruption of c-Src impairs cell cycle progression and tumorigenesis

“…Tyrosinephosphorylated PyVmT promotes proliferation by activating classical mitogenic signaling through the Ras-MAP kinase and PI3-kinase pathways (19,20). As SFKs phosphorylate tyrosine residues on PyVmT, loss of PyVmT tyrosine phosphorylation may explain the proliferation defect in cells lacking c-Src.…”

Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

“…The mouse mammary tumor virus (MMTV)-PyMT mammary tumor system continues to be extensively employed to examine virtually every issue that is relevant to breast cancer. The reader is also referred to earlier reviews dealing with MT (84,85,121,144,251,258).…”