HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I TAX MASKS C-MYC FUNCTION THROUGH ACAMP-DEPENDENT PATHWAY

Human T-cell leukemia virus type I Tax is a pleiotropic gene regulator that functions through CREB/ATF- and NF-kappa B-mediated pathways, In most contexts, Tax is a potent gene activator. Here, we describe an u nexpected finding of Myc repression by Tax. In cells that overexpress human T-cell leukemia virus type I Tax, the detection of c-Myc protein in the nucleus by a monoclonal antibody was masked. Tax prevented imm unological visualization of a Myc epitope contained within amino acids 45-104, resulting in interference with Myc function in transcription and in anchorage-independent cell growth, Tax did not affect steady-st ate protein levels since detection of c-Myc with other antibodies was unperturbed. Four observations suggest that this Tax-Myc interaction i s mediated through CREB/ATF signal transduction. 1) Tax point mutants, selectively defective for activation of CREB/ATF but not NF-kappa B, failed to mask. c-Myc; 2) masking of Myc was abolished when Tax-expres sing cells were treated with protein kinase inhibitor H-9; 3) Tax-spec ific shielding of Myc is absent in cells (B1R) that are genetically de fective for cAMP signaling; and 4) forskolin treatment of cells mimick ed Tax in masking the Myc epitope, Considered collectively, these find ings suggest a regulation of Myc function at the level of localized pr otein conformation.