Critical Role for SV40 Small-t Antigen in Human Cell Transformation

Abstract

Defining the ability of simian virus 40 (SV40) to transform human cells has become of even greater importance with the increased understanding that this virus may play a role in some human malignancies. This report documents the requirement for viral small-t (ST) antigen in large-T (LT)-driven transformation of primary fibroblasts, a requirement that cannot be met by a well-known oncogene, c-Ha-ras (EJ-ras), which can cooperate with LT in rodent systems. The cellular gene telomerase is not essential for transformation, although transformed clones are not immortal without it. Similarly, an immortal mesothelial cell line has been developed using LT and telomerase. Immortalized mesothelial cells are morphologically normal, but can be transformed by introduction of ST, or ST + ras, but not by ras alone. It is likely that ST will be required along with LT for transformation of most human cell types.

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

“…Our demonstration that inhibition of PP-1 activity by okadaic acid and calyculin A induces strong hyperphosphorylation of p53 and also activates its transcriptional activity in SV40 large-T transformed HLECs suggests that SV 40 large-T suppression of p53 may require dephosphorylation of p53 by . In this regard, it is interesting to note that transformation of human diploid fibroblasts and epithelial cells requires inhibition or alteration of PP-2A by SV 40 small T (Yu et al, 2001;Hahn et al, 2002). In addition, transformation requires inactivation of p53 and Rb by complex formation with SV 40 large-T (Yu et al, 2001;Hahn et al, 2002;Walter, 2003).…”

“…In this regard, it is interesting to note that transformation of human diploid fibroblasts and epithelial cells requires inhibition or alteration of PP-2A by SV 40 small T (Yu et al, 2001;Hahn et al, 2002). In addition, transformation requires inactivation of p53 and Rb by complex formation with SV 40 large-T (Yu et al, 2001;Hahn et al, 2002;Walter, 2003). Together, these results suggest that both PP-1 and PP-2A are involved in regulation of cell transformation and thus carcinogenesis.…”

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

“…In addition, the coexpression of LT and hTERT with an oncogenic allele of the H-Ras gene can successfully induce cell transformation in rodent cell models (Michalovitz et al, 1987;Hirakawa and Ruley, 1988). However, human cells expressing LT, hTERT and H-Ras cannot grow in an anchorage-independent manner or form tumors in animals without the additional introduction of ST (Hahn et al, 1999(Hahn et al, , 2002Yu et al, 2001). Several lines of evidence suggest that ST perturbs cellular targets that participate in human tumor development (Shenk et al, 1976;Crawford et al, 1978;Choi et al, 1988).…”

SV40 reporter viruses

“…These cells express LT and ST from integrated viral DNA that cannot replicate because of a defective origin of replication. Some experiments were done using 5ADL, a persistently infected human mesothelial cell culture (Fahrbach et al, 2008;Yu et al, 2001) that contains episomal DNA of the virus DL-888 (Shenk et al, 1976). DL-888 expresses LT but not ST because of a small deletion across the ST splice donor sequence.…”