This proposal continues studies directed to the elucidation of cellular mechanisms of gene regulation which are related to the neoplastic process in humans. We are specifically studying ectopic protein synthesis in human cancer because it offers a good experimental model for investigating this problem. The ectopic synthesis of placental proteins by non-trophoblastic neoplasms is of special interest because of similar properties of rapid growth, invasiveness, and avoidance of immune detection of neoplastic cells and trophoblastic cells. We are conducting experiments in the following categories: (1) The expression of gene products in a tissue specific, developmentally programmed and hormone inducible manner is controlled by specific promotor and enhancer sequences within the gene. The region of DNA upstream from the transcriptional start of each of the alkaline phosphatase isoenzyme genes will be isolated and sequenced, and specific enhancers identified by testing native and mutated 5'-flanking regions in a transient expression assay. This will allow direct comparison of the sequence elements controlling tissue specific and temporal expression at the alkaline phosphatase family to other similarly regulated genes. (2) Regulation of embryonic gene expression, comparing the factors of malignancy, phenotype, and differentiation. These will examine transcriptional regulation of ectopic embryonic versus phenotypic proteins synthesis in a system of breast carcinoma cells in which the promotion of differentiation by 1,25 dihydroxyvitamin D3 switches off the embryonic and augments the phenotypic enzyme. These studies will also examine the regulation of the switch from a fetal to of placental proteins and the specific messages for these proteins will be examined in choriocarcinoma cells and in non-trophoblastic tumor cell lines in which the placental proteins are synthesized. The purpose of these studies is to determine whether similar regulatory mechanisms are operant. (3) Studies of trophoblast surface proteins which are re-expressed in malignancy and which are essential to cell viability and proliferation. These are continuation studies of the transferrin receptor and ferrin receptor which are trophoblastic membrane receptors important for iron metabolism and regulators of cellular proliferation. The goal of these studies will be to investigate the relationship of these receptors in the regulation of iron incorporation by the trophoblast.
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