HTLV-I Tax mutants that do not induce GI arrest are disabled in activating the anaphase promoting complex

HTLV-1 Tax is a potent activator of viral transcription and NF-kappa B. Recent data indicate that Tax activates the anaphase promoting complex/cyclosome (APC/C) ahead of schedule, causing premature degradation of cyclin A, cyclin B1, securin, and Skp2. Premature loss of these mitotic regulators is accompanied by mitotic aberrations and leads to rapid senescence and cell cycle arrest in HeLa and S. cerevisiae cells. Tax-induced rapid senescence (tax-IRS) of HeLa cells is mediated primarily by a dramatic stabilization of p27(KIP) and is also accompanied by a great surge in the level of p21(CIPI)mRNA and protein. Deficiencies in p27(KIP) prevent Tax-IRS. A collection of tax point mutants that permit normal growth of S. cerevisiae have been isolated. Like wild-type tax, many of them (C23W, A108T, L159F, and L235F) transactivate both the HTLV-LTR and the NF-kappa B reporters. One of them, V19M, preferentially activates NF-kappa B, but is attenuated for LTR activation. None of the mutants significantly elevated the levels of p21(CIPI) and p27(KIPI), indicating that the dramatic surge in p21(CIPI/WAFI) and p27(KIPI) induced by Tax is brought about by a mechanism distinct from NF-kappa B or LTR activation. Importantly, the ability of these mutants to activate APC/C is attenuated or abrogated. These data indicate that Tax-induced rapid senescence is causally associated with APC/C activation.