Distinct p300-responsive mechanisms promote caspase dependent apoptosis byhuman T-cell lymphotropic virus type 1 Tax protein

The dysregulation of cellular apoptosis pathways has emerged as a critical early event associated with the development of many types of human cancers. Numerous viral and cellular oncogenes, aside from their inherent transform ing properties, are known to induce programmed cell death, consistent with the hypothesis that genetic defects are required to support tumor survival. Here, we report that nuclear expression of the CREB-binding protein (CBP)/ p300-binding domain of the human T-cell lymphotropic virus type 1 (HTLV-1) transactivator, Tax, triggers an apoptotic death-inducing signal during sho rt-term clonal analyses, as well as in transient cell death assays. Coexpre ssion of the antiapoptotic factor Bcl-2 increased serum stimulation; incuba tion with the chemical caspase inhibitor z-Val-Ala-DL-Asp fluoromethylketon e antagonized Tax-induced cell death. The CBP/p300-binding defective Tax mu tants K88A and V89A exhibited markedly reduced cytotoxic effects compared t o the wild-type Tax protein. Importantly, nuclear expression of the minimal CBP/p300-binding peptide of Tax induced apoptosis in the absence of Tax-de pendent transcriptional activities, while its K88A counterpart did not caus e cell death. Further, Tax-mediated apoptosis was effectively prevented by ectopic expression of the p300 coactivator. We also report that activation of the NF-kappaB transcription pathway by Tax, under growth arrest conditio ns, results in apoptosis that occurs independent of direct Tax coactivator effects. Our results allude to a novel pivotal role for the transcriptional coactivator p300 in determining cell fate and raise the possibility that d ysregulated coactivator usage may pose an early barrier to transformation t hat must be selectively overcome as a prerequisite for the initiation of ne oplasia.