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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1490-1497.
Prepublished online as a Blood First Edition Paper on May 20, 2004; DOI 10.1182/blood-2003-12-4174.
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NEOPLASIA
HTLV-I Tax induces a novel interaction between p65/RelA and p53 that results in inhibition of p53 transcriptional activity
Soo-Jin Jeong,
Michael Radonovich,
John N. Brady, and
Cynthia A. Pise-Masison
From the Virus Tumor Biology Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Nuclear factor  B (NF-B) activation plays a critical role in oncogenesis by human T-cell lymphotrophic virus type I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL), and is indispensable for maintenance of the malignant phenotype. In T lymphocytes, Tax-mediated p53 inhibition is dependent on Tax activation of the NF-B pathway and is linked to p53 phosphorylation. We now report that blocking NF-B transcriptional activation in HTLV-I–transformed cells restores p53 activity. Further, using mouse embryo fibroblast (MEF) null cells and antisense oligonucleotides to inhibit expression of NF-B family members, we demonstrate that the p65 subunit of NF-B is uniquely involved in p53 inhibition. Coimmunoprecipitation assays demonstrate an interaction between p65 and p53 in HTLV-I–transformed cells. In transient transfection assays, we demonstrate that Tax induces the p53-p65 interaction. Phosphorylation of p53 at serines 15 and 392 is critical for complex formation. Importantly, Tax-mediated p53 inhibition correlates with p65 and p53 interaction. By using chromatin immunoprecipitation (ChIP) assays, we find that in HTLV-I–transformed cells p53 and p65 form a complex on the inactive, p53-responsive murine double minute 2 (MDM2) promoter. Consistent with reduced transcriptional activity, transcription factor IID (TFIID) binding is not observed. These studies identify a unique mechanism for p53 regulation by the p65/RelA subunit of NF-B.
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