DIFFERENCES IN SUSCEPTIBILITY TO APOPTOSIS EXHIBITED BY TAX-POSITIVE AND TAX-NEGATIVE MOUSE FIBROBLAST CELL LINES.

Abstract

P052 Human T lymphotropic virus type I (HTLV-I) is the etiological agent of adult T cell leukemia (ATL). Numerous studies indicate that the viral transactivator Tax contributes to HTLV-I-associated immortalization and malignant transformation. Tax is a nuclear protein that not only trans-activates its own enhancer in the long terminal repeat (LTR) promoter, but also modulates the expression of several cellular genes. We have observed that fibroblast cell lines from tail biopsies of tax-transgenic mice form foci in vitro, grow as tumors in nude mice, and show upregulated c-myc expression; control cells from non-transgenic mice do not exhibit these properties. Evidence that certain nuclear oncogenes, including c-myc, can induce apoptotic cell death under certain conditions prompted us to asses the susceptibility of our fibroblast cell lines to induction of apoptosis by using two different apoptotic stimuli: serum deprivation and TNF a treatment We found that Tax-negative cells rapidly lose their viability after serum deprivation. In contrast, Tax-expressing cells remain viable even after 72 hours of serum starvation. While Tax-negative cells round-up and detach from the substrate under low-serum conditions, these morphological alterations are absent or less evident in Tax-expressing cells. Serum starvation of Tax-negative cells for 48 hours results in enhanced fragmentation of DNA; this hallmark of apoptosis is much less evident in Tax-positive cells. On the contrary, TNFa treatment is more effective in inducing apoptotic cell death in Tax-positive than in Tax-negative cells. Our data indicate that, while Tax protects mouse fibroblasts from the apoptotic death induced by serum deprivation, it enhances TNFa-mediated apoptosis; thus, it appears that Tax can exerts either a protective or enhancing effect on programmed cell death, depending on the apoptotic stimuli used. The molecular mechanisms involved in the observed anti- and pro-apoptotic activity of Tax are under investigation.