HTLV-1 Tax mutants that do not induce G1 arrest are disabled in activating the anaphase promoting complex.
HTLV-1 Tax is a potent activator of viral transcription and NF-kappaB. 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 p27KIP and is also accompanied by a great surge in the level of p21CIP1mRNA and protein. Deficiencies in p27KIP 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-kappaB reporters. One of them, V19M, preferentially activates NF-kappaB, but is attenuated for LTR activation. None of the mutants significantly elevated the levels of p21CIP1and p27KIP1, indicating that the dramatic surge in p21CIP1/WAF1and p27KIP 1induced by Tax is brought about by a mechanism distinct from NF-kappaB 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.
Merling
Randall
R
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. rmerling@usuhs.mil
Chen
Chunhua
C
Hong
Sohee
S
Zhang
Ling
L
Liu
Meihong
M
Kuo
Yu-Liang
YL
Giam
Chou-Zen
CZ
D019943:Amino Acid Substitution; D064173:Anaphase-Promoting Complex-Cyclosome; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase; D016355:Genes, pX; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000096:biosynthesis; D017354:Point Mutation; D012367:RNA, Viral / Q000096:biosynthesis; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000254:growth & development; D020079:Terminal Repeat Sequences; D015533:Transcriptional Activation; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012367:RNA, Viral; D050760:Cyclin-Dependent Kinase Inhibitor p27; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome