HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule.
Expression of the human T lymphotropic virus type I (HTLV-I) transactivator/oncoprotein, Tax, leads to faulty mitosis as reflected by chromosome aneuploidy, cytokinesis failure, and formation of micro- and multinucleated cells. Here we show that HTLV-I-transformed T cells progress through S/G(2)/M phases of the cell cycle with a delay. This delay is correlated with a decrease in the levels of cyclin A, cyclin B1, and securin. In tax-expressing cells, the Cdc20-associated anaphase promoting complex (APC(Cdc20)), an E3 ubiquitin ligase that controls metaphase to anaphase transition, becomes active before cellular entry into mitosis as evidenced by premature cyclin B1 polyubiquitination and degradation during S/G(2). Consistent with the notion that Tax activates APC(Cdc20) directly, Tax is found to coimmunoprecipitate with Cdc20 and Cdc27/APC3. The APC(Cdc20) activity prematurely activated by Tax remains sensitive to spindle checkpoint inhibition. Unscheduled activation of APC(Cdc20) by Tax provides an explanation for the mitotic abnormalities in HTLV-I-infected cells and is likely to play an important role in the development of adult T cell leukemia.
Liu
Baoying
B
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Hong
Sohee
S
Tang
Zhanyun
Z
Yu
Hongtao
H
Giam
Chou-Zen
CZ
D064173:Anaphase-Promoting Complex-Cyclosome; D064199:Cdc20 Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D064249:Securin; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
C534699:CCNB1 protein, human; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D016356:Gene Products, tax; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D025821:Polyubiquitin; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome