HTLV-I Tax induces a novel interaction between p65/RelA and p53 that results in inhibition of p53 transcriptional activity.
Nuclear factor kappaB (NF-kappaB) 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-kappaB pathway and is linked to p53 phosphorylation. We now report that blocking NF-kappaB 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-kappaB family members, we demonstrate that the p65 subunit of NF-kappaB 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-kappaB.
Jeong
Soo-Jin
SJ
Virus Tumor Biology Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute/NIH, Bldg 41/B303, 41 Library Drive, Bethesda, MD 20892, USA.
Radonovich
Michael
M
Brady
John N
JN
Pise-Masison
Cynthia A
CA
D000818:Animals; D002472:Cell Transformation, Viral; D004257:DNA Polymerase II / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology / Q000821:virology; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics*; D015490:HTLV-I Infections / Q000503:physiopathology* / Q000821:virology; D015368:Human T-lymphotropic virus 1; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051996:Transcription Factor RelA; D035362:Transcription Factor TFIID / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D004257:DNA Polymerase II; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D016376:Oligonucleotides, Antisense; D017346:Protein Serine-Threonine Kinases; D051996:Transcription Factor RelA; D035362:Transcription Factor TFIID; D016159:Tumor Suppressor Protein p53; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse