Human T-cell leukemia virus type 1 is an oncogenic retrovirus etiologically causal of adult T-cell leukemia. The virus encodes a Tax oncoprotein, which functions in transcriptional regulation, cell cycle control, and transformation. Because adult T-cell leukemia is a highly virulent cancer that is resistant to numerous chemotherapeutic treatments, to understand better this disease it is important to comprehend how human T-cell leukemia virus type 1 promotes cellular growth and survival. Most of the existing data point to Tax activation of NF-B as important for cellular proliferation and transformation. We show here that Tax, in the absence of NF-B signaling, can activate activator protein-1 to promote cellular proliferation and survival. Tax is shown to activate activator protein-1 through the phosphatidylinositol 3-kinase/Akt pathway.Many of the molecular alterations associated with carcinogenesis occur in cell signaling pathways that regulate cell proliferation and differentiation. Human T-cell leukemia virus type 1 (HTLV-1) 2 is the etiological agent for adult T-cell leukemia (ATL), an aggressive human T-cell malignancy (1-4). The mechanisms of ATL leukemogenesis are not yet fully understood. However, viral protein expression early in infection probably plays a major role for disease development (5-7).HTLV-1 encodes a 40-kDa nuclear oncoprotein, Tax (8, 9). There is strong evidence, including results from transgenic mice, that Tax plays an important role in cellular transformation (10 -12). A current view is that cellular transformation by HTLV-1 is linked to the capacity of Tax to deregulate cellular signaling pathways (13)(14)(15)(16)(17)(18)(19), to disrupt the cell's genetic integrity (20 -22), and to perturb cellular gene expression in part through activation of transcription factors such as NF-B and activator protein-1 (AP-1) (17,23,24). Aberrant activation of these signal transducers and their downstream mediators can provoke uncontrolled cell growth and malignant transformation (14,15,17). HTLV-1 infection can also trigger a hyperinflammatory host response leading to connective tissue diseases, such as rheumatoid arthritis, tropical spastic paraparesis, and HTLV-associated myelopathy (25, 26).Akt or protein kinase B (Akt/PKB) is a serine/threonine protein kinase that functions as a regulator of cell survival and proliferation (27)(28)(29)(30)(31). Akt/PKB is activated by PI3K through site-specific phosphorylation. Full activation of Akt requires phosphorylation of Ser 473 (31,32), and the actual mechanism of activation remains somewhat controversial and is not completely understood. Some have suggested that Akt could be activated in a PI3K-independent manner (31, 32), but the physiological significance of these findings remains poorly established. Aktbinding proteins have also been reported to regulate Akt activity (29). For example, the carboxyl-terminal modulator protein inhibits signaling by direct binding to Akt, leading to reduced phosphorylation at its Ser 473 residue. By contrast, proteins like...