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Molecular and Cellular Biology, August 2003, p. 5269-5281, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5269-5281.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human T-Lymphotropic Virus Type 1 Oncoprotein Tax Promotes Unscheduled Degradation of Pds1p/Securin and Clb2p/Cyclin B1 and Causes Chromosomal Instability

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814,¹ Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6701 Szeged, Hungary,² Department of Molecular Microbiology, Faculty of Medicine, Technion-Israel Institute of Technology, Bat-Galim, Haifa 31096, Israel,³ Institute for Molecular and Human Genetics, Georgetown University, Washington, D.C. 20057⁴

Received 15 November 2002/ Returned for modification 14 January 2003/ Accepted 28 April 2003

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia. The HTLV-1 transactivator, Tax, is implicated as the viral oncoprotein. Naïve cells expressing Tax for the first time develop severe cell cycle abnormalities that include increased DNA synthesis, mitotic arrest, appearance of convoluted nuclei with decondensed DNA, and formation of multinucleated cells. Here we report that Tax causes a drastic reduction in Pds1p/securin and Clb2p/cyclin B levels in yeast, rodent, and human cells and a loss of cell viability. With a temperature-sensitive mutant of the CDC23 subunit of the anaphase-promoting complex (APC), cdc23^ts; a temperature-sensitive mutant of cdc20; and a cdh1-null mutant, we show that the diminution of Pds1p and Clb2p brought on by Tax is mediated via the Cdc20p-associated anaphase-promoting complex, APC^Cdc20p. This loss of Pds1p/securin and Clb2p/cyclin B1 occurred before cellular entry into mitosis, caused a G₂/M cell cycle block, and was accompanied by severe chromosome aneuploidy in both Saccharomyces cerevisiae cells and human diploid fibroblasts. Our results support the notion that Tax aberrantly targets and activates APC^Cdc20p, leading to unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1, a delay or failure in mitotic entry and progression, and faulty chromosome transmission. The chromosomal instability resulting from a Tax-induced deficiency in securin and cyclin B1 provides an explanation for the highly aneuploid nature of adult T-cell leukemia cells.

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