Disease relevance of HpVgp2

• Properties of cells transformed by the middle T-antigen-coding region of polyomavirus [1].
• As a first step toward assessing the role of individual c-Src family tyrosine kinases in PyV middle T antigen-induced mammary tumorigenesis, we have crossed transgenic mice carrying the mouse mammary tumor virus (MMTV)/PyV middle T antigen fusion gene with mice bearing a disrupted c-src proto-oncogene [2].
• Middle T antigen (PymT) is the principal transforming component of polyomavirus, and rapidly induces hemangiomas in neonatal mice [3].
• Middle T antigen expressed in human cells by a recombinant adenovirus was detected primarily in the membrane skeleton [4].
• This in vitro-constructed retrovirus, SRMT1, is a variant of Rous sarcoma virus that encodes the middle T antigen in place of v-src [5].

High impact information on HpVgp2

• The phosphorylation of proteins on tyrosine in vivo and in vitro was examined in 3T3 cells stimulated by platelet-derived growth factor (PDGF) and transformed by polyoma middle T antigen (MTAg) by using an antibody directed against phosphotyrosine (P-tyr) [6].
• Expression of the middle-T antigen of polyomavirus is sufficient to induce transformation of fibroblasts in culture and tumour formation in whole animals [7].
• This growth disturbance was correlated with elevated expression of the PyV middle T antigen and the activation of the PyV middle T antigen-associated c-Yes tyrosine kinase [2].
• Taken together, these findings suggest that c-Src tyrosine kinase activity is required for PyV middle T antigen-induced mammary tumorigenesis and also illustrate an in vivo genetic approach to the dissection of mitogenic signal transduction pathways [2].
• Since it is the purpose of this review to consider the natural function of middle T antigen (MT), encoded by one of the seemingly crucial transforming genes of polyomavirus, we will reconsider and redefine the virus and its MT gene in the context of its natural biology and function [8].

Chemical compound and disease context of HpVgp2

• Identification of the threonine phosphorylation sites on the polyomavirus major capsid protein VP1: relationship to the activity of middle T antigen [9].
• Polyomavirus middle T antigen (MT) is phosphorylated on serine residues [10].
• These results suggest that association of the polyomavirus middle T antigen with PtdIns 3-kinase activates a distinct inositol metabolic pathway [11].
• Mutation of a cysteine residue in polyomavirus middle T antigen abolishes interactions with protein phosphatase 2A, pp60c-src, and phosphatidylinositol-3 kinase, activation of c-fos expression, and cellular transformation [12].
• Phosphorylation of src and MTAg is reduced in polyomavirus and MTAg- transformed cells pretreated with herbimycin A [13].

Biological context of HpVgp2

• Cloned polyomavirus genomes encoding the small T antigen or truncated forms of the middle T antigen facilitated the growth of genomes encoding only the large T antigen in mouse 3T6 cells [14].
• We have obtained antibodies specific for the polyoma virus middle-size tumor antigen (middle T antigen) by immunizing rabbits with a synthetic peptide, Lys-Arg-Ser-Arg-His-Phe, corresponding to the six carboxy-terminal amino acids of the middle T antigen predicted from the nucleotide sequence of polyoma DNA [15].
• Polyoma middle T antigen requires cooperation from another gene to express the malignant phenotype in vivo [16].
• Plasmids expressing partial adenovirus early region 1A (E1A) coding sequences were tested for activities which facilitate in vitro establishment (immortalization) of primary baby rat kidney cells and which enable the T24 Harvey ras-related oncogene and the polyomavirus middle T antigen (pmt) gene to transform primary baby rat kidney cells [17].
• The effect of mammary gland-specific expression of the polyomavirus middle T antigen was examined by establishing lines of transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/enhancer [18].

Anatomical context of HpVgp2

• When isolated membranes are incubated with [gamma-32P]ATP, polyoma virus middle T antigen (mT) becomes phosphorylated on tyrosine [19].
• Phosphorylation of polyoma middle T antigen and cellular proteins in purified plasma membranes of polyoma virus-infected cells [19].
• The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells, leading to the formation of vascular tumors in newborn mice [20].
• Two rat thyroid epithelial differentiated cell lines, PC Cl 3 and PC myc, were infected with the polyoma murine leukemia virus (PyMLV) carrying the Middle-T-antigen gene of polyomavirus [21].
• Mammary epithelium-specific expression of polyomavirus middle T antigen results in the rapid development of multifocal metastatic mammary tumors, whereas transgenic mice expressing a mutant middle T antigen decoupled from the phosphatidylinositol 3'-OH kinase (MTY315/322F) develop extensive mammary gland hyperplasias that are highly apoptotic [22].

Associations of HpVgp2 with chemical compounds

• This suggests that the association of protein phosphatase 2A with middle T antigen may function to activate PtdIns 3-kinase [23].
• Experiments with ATP affinity reagents 8-azido-ATP and 2,3-dialdehyde ATP have failed to label the middle T antigen [24].
• Sucrose gradient fractionation revealed that the middle T antigen was associated with complexes with molecular weights of 500,000 to 1,000,000 [4].
• Further genetic dissection of this mutant reveals that substituting leucine for proline at amino acid 248 results in a completely transformation defective MTAg [25].
• At this time, expression of middle-T antigen resulted in the redistribution of shc and src to a brefeldin A resistant perinuclear compartment coincident with the formation of kinase active complexes containing middle-T antigen, shc and src [26].

Analytical, diagnostic and therapeutic context of HpVgp2

• Real-time PCR analysis revealed a consistently increased expression of septin 9 (Sept9), not only in polyomavirus middle T antigen-induced, but in a wide variety of mouse models of breast cancer [27].
• Cell fractionation in non-ionic detergent distinguishes sub-populations of polyoma virus middle T antigen and reveals a novel form [28].
• Site-directed mutagenesis of polyomavirus middle-T antigen sequences encoding tyrosine 315 and tyrosine 250 [29].
• All of the mutants produced a stable MTAg, as assessed by metabolic labeling or immunoblotting, and each mutant possessed wild-type levels of associated tyrosine kinase activity and associated phosphatidylinositol-3 (PI-3) kinase activity [30].
• EXPERIMENTAL DESIGN: We isolated five lines of transgenic mice harboring the chicken alpha-actin vascular smooth muscle enhancer/promoter linked to the polyomavirus middle T antigen using a standard microinjection protocol [31].

References