Human T-lymphotropic virus type I (HTLV-I) causes acute T-ceIl leukemia and lymphoma in a small percentage of infected individuals after a long latency period of up to 20-40 years. The mechanisms for progression from clinical latency to malignancy of T-lymphocytes are not well understood but involve the unique viral transactivator/onco-protein, Tax. The effects Tax exerts on cells are pleiotropic and include potent NF- B activation, cell cycle perturbation, and cell transformation. These effects have often been attributed to interaction of Tax with a myriad of cellular proteins involved in distinct signal transduction pathways. During the past funding period, we have discovered that Tax interacts directly with the catalytic C-subunit (PP2Ac) of the major Ser/Thr-protein phosphatase, PP2A, and reduces the enzymatic activity of PP2A by acting as a non-competitive inhibitor. Further, we have found that Tax activates G1/S entry but blocks mitosis. The Tax-induced cell cycle abnormalities may be linked to its interaction with PP2A and the spindle checkpoint pathway. Most unexpectedly, several of the biological effects of Tax, especially those that are related to cell cycle progression and checkpoint controls, can be recapitulated in Saccharomyces cerevisiae. We think the allosteric inhibition of PP2A and/or the alteration of the functions of PP2A by Tax play a significant role in the latter's impacts on multiple cellular regulatory processes. Further, we think the interaction between Tax and PP2A may involve other cellular proteins that determine the specific signaling pathways targeted by Tax. Finally, the cell cycle dysfunctions in spindle checkpoint control and mitosis as caused by Tax may be linked to its interaction with PP2A and the spindle checkpoint protein, MAD 1. In this application, we seek to investigate further the interaction between Tax and PP2A and their biological consequences, including mitotic exit control.
Three specific aims are proposed:
Aim 1 : Characterizations of Tax-PP2A interaction.
Aim 2 : Tax, PP2A, and cell cycle control.
Aim 3 : Use of Saccharomyces cerevisiae as a model to study cell cycle abnormalities induced by Tax.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA075688-06
Application #
6542185
Study Section
Virology Study Section (VR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1997-09-01
Project End
2007-06-30
Budget Start
2002-07-15
Budget End
2003-06-30
Support Year
6
Fiscal Year
2002
Total Cost
$278,616
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817
Giam, Chou-Zen; Jeang, Kuan-Teh (2007) HTLV-1 Tax and adult T-cell leukemia. Front Biosci 12:1496-507
Zhang, Ling; Liu, Meihong; Merling, Randall et al. (2006) Versatile reporter systems show that transactivation by human T-cell leukemia virus type 1 Tax occurs independently of chromatin remodeling factor BRG1. J Virol 80:7459-68
Liu, Baoying; Liang, Min-Hui; Kuo, Yu-liang et al. (2003) Human T-lymphotropic virus type 1 oncoprotein tax promotes unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1 and causes chromosomal instability. Mol Cell Biol 23:5269-81
Fu, De-Xue; Kuo, Yu-Liang; Liu, Bao-Ying et al. (2003) Human T-lymphotropic virus type I tax activates I-kappa B kinase by inhibiting I-kappa B kinase-associated serine/threonine protein phosphatase 2A. J Biol Chem 278:1487-93
Liang, Min-Hui; Geisbert, Thomas; Yao, Yao et al. (2002) Human T-lymphotropic virus type 1 oncoprotein tax promotes S-phase entry but blocks mitosis. J Virol 76:4022-33
Kuo, Y L; Tang, Y; Harrod, R et al. (2000) Kinase-inducible domain-like region of HTLV type 1 tax is important for NF-kappaB activation. AIDS Res Hum Retroviruses 16:1607-12
Nicot, C; Harrod, R (2000) Distinct p300-responsive mechanisms promote caspase-dependent apoptosis by human T-cell lymphotropic virus type 1 Tax protein. Mol Cell Biol 20:8580-9
Harrod, R; Kuo, Y L; Tang, Y et al. (2000) p300 and p300/cAMP-responsive element-binding protein associated factor interact with human T-cell lymphotropic virus type-1 Tax in a multi-histone acetyltransferase/activator-enhancer complex. J Biol Chem 275:11852-7
Tang, Y; Tie, F; Boros, I et al. (1998) An extended alpha-helix and specific amino acid residues opposite the DNA-binding surface of the cAMP response element binding protein basic domain are important for human T cell lymphotropic retrovirus type I Tax binding. J Biol Chem 273:27339-46