| Popis: |
Human T-lymphotropic retrovirus type I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATL) and tropical spastic paraparesis (TSP) or HTLV-I associated myelopathy (HAM). The 3′ end of the HTLV-I genome encodes a transactivator, Tax, that stimulates transcription from the viral LTR. In addition to its essential role in viral replication, Tax activates transcription of various cellular genes involved in mediating cell growth. The ability of Tax to alter viral and cellular gene expression appears to be causally related to ATL and TSP/HAM. Our research efforts have focused on elucidating the molecular mechanism of Tax function. We previously demonstrated that CREB, a cellular DNA binding protein of the bZip family activates transcription from the HTLV-I LTR synergistically with Tax. Three cellular proteins that bind specifically to the cAMP response element (CRE) in the HTLV-I 21 bp repeats were subsequently identified. These three binding proteins are composed of homodimers and a heterodimer formed by CREB and a highly related protein, ATF-1. Tax was shown to interact specifically with the CREB subunit in CREB homodimer and CREB:ATF-1 heterodimer. Sequence comparison and domain switching between CREB and ATF-1 indicate that Tax interacts specifically with the s p282AAR residues near the conserved DNA binding domain of CREB. The Tax:CREB complex exhibits increased DNA recognition specificity and assembles preferentially on CRE motif flanked by 5′ G rich and 3′ C rich sequences present in the viral 21 bp repeats. The tethering of Tax to the viral enhancer via CREB is crucial for Tax transactivation. Characterization of Tax mutants further indicates that the structural integrity in the NH2-terminus of Tax is crucial for its interaction with CREB and support the notion that a transactivation domain resides in the COOH-terminal region of Tax. These results suggest a model whereby the recruitment of Tax via CREB to the HTLV-I enhancer facilitates the interaction between the transactivation domain of Tax and the basal transcriptional machinery leading to increased HTLV-I gene expression. |
