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.
