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Molecular and Cellular Biology, November 2000, p. 8580-8589, Vol. 20, No. 22
Basic Research Laboratory, Division of Basic
Sciences, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland 20892
Received 2 May 2000/Returned for modification 9 June 2000/Accepted 21 August 2000
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 transforming 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 short-term clonal analyses, as
well as in transient cell death assays. Coexpression of the
antiapoptotic factor Bcl-2 increased serum stimulation; incubation with
the chemical caspase inhibitor z-Val-Ala-DL-Asp
fluoromethylketone antagonized Tax-induced cell death. The
CBP/p300-binding defective Tax mutants K88A and V89A exhibited markedly
reduced cytotoxic effects compared to the wild-type Tax protein.
Importantly, nuclear expression of the minimal CBP/p300-binding peptide
of Tax induced apoptosis in the absence of Tax-dependent
transcriptional activities, while its K88A counterpart did not cause
cell death. Further, Tax-mediated apoptosis was effectively prevented
by ectopic expression of the p300 coactivator. We also report that
activation of the NF-
0270-7306/00/$04.00+0
Distinct p300-Responsive Mechanisms Promote
Caspase-Dependent Apoptosis by Human T-Cell Lymphotropic Virus
Type 1 Tax Protein
B transcription pathway by Tax, under growth
arrest conditions, 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 dysregulated coactivator usage may pose
an early barrier to transformation that must be selectively overcome as
a prerequisite for the initiation of neoplasia.
*
Corresponding author. Mailing address: Basic Research
Laboratory, Division of Basic Sciences, National Cancer Institute,
National Institutes of Health, Building 41, Room D804, 9000 Rockville
Pike, Bethesda, MD 20892. Phone: (301) 402-0303. Fax: (301) 402-0055. E-mail: cbeben{at}helix.nih.gov.
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