Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence.
The human T-lymphotropic virus type 1 (HTLV-1) Tax binds the anaphase promoting complex (APC) and activates it ahead of schedule. Here, we show that APC activation by Tax induces rapid senescence (tax-IRS) independently of p53 and pRB. In response to tax, cyclin A, cyclin B1, securin, and Skp2 becomes polyubiquitinated and degraded starting in S phase. This is followed by a surge in p21(CIP1/WAF1) and p27(KIP1) in mid to late S and G2/M leading to a permanent G1 arrest. Tax-positive HTLV-1-transformed T-cell lines express elevated levels of p21(CIP1/WAF1), but low levels of p27(KIP1). Finally, Tax can be stably expressed in p27(KIP1)-null NIH3T3 cells. These results indicate that APC activation by Tax causes inactivation of SCF(Skp2) and stabilization of p21(CIP1/WAF1) and p27(KIP1). The build-up of p21(CIP1/WAF1) and especially p27(KIP1) commits cells to senescence. Evading tax-IRS through a loss of p27(KIP1) function is likely to be critical for cell transformation by Tax and development of adult T-cell leukemia after HTLV-1 infection. Finally, activation of APC ahead of schedule may be exploited to arrest cancer cell growth.
Kuo
Yu-Liang
YL
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Giam
Chou-Zen
CZ
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D002472:Cell Transformation, Viral; D016922:Cellular Senescence / Q000502:physiology*; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D064249:Securin; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016356:Gene Products, tax; D009363:Neoplasm Proteins; D044786:S-Phase Kinase-Associated Proteins; D064249:Securin; D016159:Tumor Suppressor Protein p53; C578002:pituitary tumor-transforming protein 1, human; D025821:Polyubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome