Overproduction of NFKB2 (lyt-10) and c-Rel: a mechanism for HTLV-I Tax-mediated trans-activation via the NF-kappa B signalling pathway.
Molecular, biochemical and epidemiological evidence implicate HTLV-I as an etiologic agent of adult T cell leukemia (ATL). The Tax protein of HTLV-I, a positive transcriptional activator of HTLV-I gene expression, is a viral oncogene that also increases transcription of cellular genes including GM-CSF, IL-2R alpha and IL-2. One of the cellular targets of the trans-activating effects of Tax is the NF-kappa B/Rel family of transcription factors, pleiotropic regulators of immunoregulatory, cytokine and viral gene expression. In this report, we demonstrate that NFKB2 (lyt-10) and c-Rel are overexpressed in HTLV-I infected and Tax-expressing cells and, together, account for the majority of the constitutive NF-kappa B binding activity in these cells before and after PMA stimulation. Most importantly, we show a Tax-dependent correlation between expression of NFKB2(p100) and processing to the DNA binding NFKB2(p52) form, induction of c-Rel, and trans-activation of NF-kappa B-mediated gene expression. Furthermore, the NFKB2 precursor is physically associated with c-Rel and with Tax in HTLV-I infected cells. We propose that NFKB2 synthesis and processing allows continuous nuclear expression of an otherwise cytoplasmic protein and, in conjunction with overexpression of c-Rel, NFKB2 alters the NF-kappa B signalling pathway and contributes to leukemic transformation of T cells by HTLV-I.
Lanoix
J
J
Terry Fox Molecular Oncology Group, Abe Stern Cancer Research Laboratory, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Lacoste
J
J
Pepin
N
N
Rice
N
N
Hiscott
J
J
D001483:Base Sequence; D002460:Cell Line; D002472:Cell Transformation, Viral; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000235:genetics*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D009838:Oligodeoxyribonucleotides; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000382:microbiology; D015533:Transcriptional Activation
D016356:Gene Products, tax; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel