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Molecular and Cellular Biology, May 2000, p. 3377-3386, Vol. 20, No. 10
0270-7306/00/$04.00+0

Inactivation of p53 by Human T-Cell Lymphotropic Virus Type 1 Tax Requires Activation of the NF-kappa B Pathway and Is Dependent on p53 Phosphorylation

Cynthia A. Pise-Masison,1,* Renaud Mahieux,1 Hua Jiang,1 Margaret Ashcroft,2 Michael Radonovich,1 Janet Duvall,1 Claire Guillerm,1 and John N. Brady1

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-kappa B activation. Analysis of Tax mutants demonstrated that Tax inactivation of p53 function correlates with the ability of Tax to induce NF-kappa B but not p300 binding or CREB transactivation. The Tax-induced p53 inactivation can be overcome by overexpression of a dominant Ikappa B mutant. Tax-NF-kappa 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-kappa 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-kappa 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.

Molecular and Cellular Biology, May 2000, p. 3377-3386, Vol. 20, No. 10
0270-7306/00/$04.00+0


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