Disordered hormone secretion is a characteristic of malignant tumors. One of the commonest endocrine manifestations of malignancy is hypercalcemia. Adult T-cell leukemia, which is linked to HTLV-1, is frequently associated with elevated calcium. A parathyroid-related polypeptide hormone has been identified as the putative hypercalcemic factor. HTLV-1 appears to induce transformation by a novel mechanism as it does not encode a known oncogene product, and integrates randomly into the host genome. The HTLV-1 and HTLV-11 genomes in addition to structural proteins encode 2 unique proteins Tax and Rex. Rex is a nuclear protein which controls expression of intermediate viral mRNAs. Tax is a nuclear phosphoprotein which transactivates its own long terminal repeat as well as numerous cellular genes. This proposal will focus on the role of the HTLV-1 and -11 Tax proteins and their interactions with the hypercalcemic factor gene promoter, affording a unique model for studying the interaction of these retroviral proteins and polypeptide hormone gene expression. Specifically, cis-active elements and their cognate transacting factors, important for basal hormone expression as well as Tax, phorbol ester and proto-oncogene responsive sequences will be defined. The cell-specific interaction of the promoter with the Tax proteins will be investigated providing insight into the diverse clinical manifestations observed following retroviral infection and expression of Tax in different tissues. These results will further the understanding of endocrine mechanisms underlying development of hypercalcemia in patients harboring malignancies and could eventually lead to the design of targeted therapies.
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