The alpha-fetoprotein (AFP) gene, an important experimental system for the study of developmental gene controls, is expressed at high levels in fetal liver and yolk sac, but silenced after birth. AFP gene controls thus mediate high level transcription, tissue-specific and developmental - stage-specific gene expression, and developmental gene silencing. Many cancers reverse this silencing, either by-passing a repressor or recapitulating fetal gene controls. The AFP gene is very accessible to experimental manipulation; its extensive study in carcinogenesis makes it an unusually attractive system for analyzing fundamental gene control mechanisms. Sequence and functional analysis show the transcription control region of the AFP gene to be extraordinarily complex.
The First Aim i s to better define the AFP gene transcription control elements, by constructing plasmids containing individual control elements and transfecting them into liver-derived cells. Experiments will focus on resolving the AFP-gene repressor from the promoter and regions that control interactions between distant enhancers and promoters.
The Second Aim win analyze how these elements regulate tissue and developmental specificity of expression, by studying them in combination with heterologous gene controls.
The Third Aim will study interactions of the gene controls with several agents that repress AFP: phorbol ester, serum, and glucocorticoid. Other experiments will study how oncogenes interact with the transcription controls, and characterize oncogenes that bypass the AFP repressor.
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