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Molecular and Cellular Biology, May 2000, p. 3377-3386, Vol. 20, No. 10
Virus Tumor Biology Section, Laboratory of
Receptor Biology and Gene Expression, National Cancer Institute,
National Institutes of Health, Bethesda,
Maryland,1 and ABL, Basic Research
Program, National Cancer Institute, Frederick Cancer Research and
Development Center, Frederick, Maryland2
Received 28 December 1999/Returned for modification 31 January
2000/Accepted 14 February 2000
p53 plays a key role in guarding cells against DNA damage and
transformation. We previously demonstrated that the human T-cell lymphotropic virus type 1 (HTLV-1) Tax can inactivate p53
transactivation function in lymphocytes. The present study demonstrates
that in T cells, Tax-induced p53 inactivation is dependent upon NF-
0270-7306/00/$04.00+0
Inactivation of p53 by Human T-Cell Lymphotropic Virus Type 1 Tax Requires Activation of the NF-
B Pathway and Is
Dependent on p53 Phosphorylation
B activation. Analysis of Tax mutants demonstrated that Tax inactivation of p53 function correlates with the ability of Tax to induce NF-
B but not p300 binding or CREB transactivation. The Tax-induced p53
inactivation can be overcome by overexpression of a dominant I
B
mutant. Tax-NF-
B-induced p53 inactivation is not due to p300 squelching, since overexpression of p300 does not recover p53 activity
in the presence of Tax. Further, using wild-type and p65 knockout mouse
embryo fibroblasts (MEFs), we demonstrate that the p65 subunit of
NF-
B is critical for Tax-induced p53 inactivation. While Tax can
inactivate endogenous p53 function in wild-type MEFs, it fails to
inactivate p53 function in p65 knockout MEFs. Importantly, Tax-induced
p53 inactivation can be restored by expression of p65 in the knockout
MEFs. Finally, we present evidence that phosphorylation
of serines 15 and 392 correlates with inactivation of p53 by Tax in T
cells. This study provides evidence that the divergent NF-
B
proliferative and p53 cell cycle arrest pathways may be cross-regulated
at several levels, including posttranslational modification of p53.
*
Corresponding author. Mailing address: Laboratory of
Receptor Biology and Gene Expression, National Cancer Institute,
National Institutes of Health, Building 41/B303, Bethesda, MD 20892. Phone: (301) 435-2499. Fax: (301) 496-4951. E-mail:
masisonc{at}dce41.nci.nih.gov.
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