Herpesvirus saimiriTipGene Causes T-Cell Lymphomas in Transgenic Mice

Abstract

New World primates develop T-cell lymphomas on infection with Herpesvirus saimiri. To investigate the oncogenic potential of the Tip gene of Herpesvirus saimiri strain C488, we tried to establish transgenic mice that should express Tip under control of a constitutive promoter. Although transgene-positive embryos were found, lines could not be established. However, using a system in which the transgene has to be activated by a Cre recombinase-mediated deletion, we were able to obtain several Tip transgenic lines. At high expression levels, the mice developed T-cell lymphomas. Thus, Tip can induce lymphomas and is therefore very likely responsible for the oncogenicity of Herpesvirus saimiri.

Histone Modification Pattern of the T-Cellular Herpesvirus Saimiri Genome in Latency

“…Consistently detectable is the expression of ORF1 (stpC/tip) (16) encoding a bicistronic transcript which is translated into StpC (for Saimiri transformation-associated protein) and Tip (for tyrosine-kinase interacting protein). Both gene products are oncoproteins (26,39,59) and necessary for the transformation of T lymphocytes (1,11). Low-level transcription is detectable for ORF73 (13,49), which codes for the LANA homolog.…”

Negative regulation of Lck by Cbl ubiquitin ligase

“…Lck activation by Herpes saimari tyrosine kinase-interacting protein (TIP)-transforming protein and mutational analysis of Lck and other SFKs has established that their unregulated activity results in oncogenicity (6,7). Thus, precise regulation of Lck is vital for physiological function.…”

Herpesvirus Ateles Tio Can Replace Herpesvirus Saimiri StpC and Tip Oncoproteins in Growth Transformation of Monkey and Human T Cells

“…In the future, this finding may be substantiated in vivo by infection of susceptible primates or by transgenic studies (35,50). Specific mutants will help to analyze the role of interacting cellular proteins and posttranslational modifications for the signal-transducing and transforming properties of Tio.…”

“…The oncogenic properties of StpC, which have been documented by transformation of rodent fibroblasts and by induction of epithelial tumors in transgenic mice, do not appear to be T-cell specific (30,45). In contrast, Tip is lethal in early embryonic stages of transgenic mice but induces a lymphomalike disease in mice when its expression is turned on only after birth (50). Tip is known to interact primarily with Lck (9), the major T-cell nonreceptor tyrosine kinase.…”