In recent years, the human T-cell leukemia virus type 1 (HTLV-1) has become increasingly recognized as an important cause for public health concern throughout the world.
HTLV-1 is the causative agent of a variety of clinical diseases, including an aggressive and fatal cancer called adult T-cell leukemia, and a neurological disorder that is clinically very similar to multiple sclerosis. A large body of evidence suggests that the clinical manifestations of HTLV-1 infection occur as a consequence of a virally-encoded protein called Tax. Our laboratory focuses on defining the intracellular consequences of Tax expression in the infected human cell, with emphasis on the Tax-dependent events that lead to malignant transformation.
The human T-cell leukemia virus (HTLV-I) is associated with a variety of clinical disorders, including an aggressive and fatal malignancy called adult T-cell leukemia (ATL). It is estimated that between 11 and 20 million people worldwide are infected with HTLV-I, and while most infected individuals remain asymptomatic, a small percentage develop ATL. A single HTLV-I-encoded protein, called Tax, has been strongly implicated in the etiology of the disease. Tax is critical to the viral life cycle, as it activates HTLV-I transcription. Recent studies demonstrate that the cellular coactivator CBP/p300 associates with Tax to potentiate transcriptional activation of the viral genome. CBP/p300 is a coactivator that regulates transcription through interaction with a wide variety of structurally unrelated transcription factors. CBP/p300 belongs to a novel class of recently described transcriptional coactivators proteins that possess histone acetyltransferase (HAT) activity, and appear to play a role in gene-specific activation through modulation of chromatin structure. Although the precise role of the HAT activity of CBP/p300 is unknown, there is a strong link between abnormalities in acetylase function, aberrant chromatin acetylation, and human cancers. These observations suggest that alterations in expression of CBP/p300 expression and/or function is a common denominator in many human malignancies, especially leukemias.
The strong correlation between CBP/p300 deregulation and human malignancies forms the basis for the premise that the physical interaction between CBP/p300 and Tax plays a causal role in neoplastic transformation of the HTLV-I infected T-cell. Our laboratory is exploring CBP/p300 transcription function using both in vitro and in vivo approaches. Our methods should allow biochemical dissection of the Tax-CBP/p300 interactions that accompany transcriptional activation. The outcome of our research may reveal basic aspects of CBP/p300 and Tax function as they pertain to gene regulation, chromatin structure, and leukemogenesis.