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.
Mori, N; Prager, D (1997) Activation of the interleukin-10 gene in the human T lymphoma line HuT 78: identification and characterization of NF-kappa B binding sites in the regulatory region of the interleukin-10 gene. Eur J Haematol 59:162-70 |
Mori, N; Kashanchi, F; Prager, D (1997) Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. Blood 90:4924-32 |
Mori, N; Prager, D (1996) Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins. Blood 87:3410-7 |
Mori, N; Prager, D (1996) High levels of AP-2-binding activity in cell lines infected with human T-cell leukemia virus type I: possible enhancement of AP-2 binding by human T-cell leukemia virus type I tax. Cancer Res 56:779-82 |
Mori, N; Gill, P S; Mougdil, T et al. (1996) Interleukin-10 gene expression in adult T-cell leukemia. Blood 88:1035-45 |