REGULATION OF GROWTH FACTORS AND MAMMALIAN EMBRYOGENESIS

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The mechanisms that regulate the production of growth factors are poorly understood. Embryonal carcinoma (EC) cells, which differentiate in vitro and mimic important stages of early mammalian development, can be used to address this issue. Differentiation of EC cells suppresses the production of two different growth factors, one related to fibroblast growth factor (referred to as FGF-related growth factor) and one related to platelet- derived growth factor (referred to as PDGF-related growth factor). Conversely, differentiation of EC cells leads to an increase in the number of receptors able to bind PDGF, FGF, and two other growth factors. These findings and others indicate that EC cells and their differentiated cells provide a powerful model system for studying the molecular mechanisms that control the production of several growth factors and their receptors. Efforts to identify the gene that codes for the FGF-related growth factor led tot he finding that EC cells express the gene for KS-FGF (a member of the FGF family of growth factors, also known as hst). In addition, we determined that differentiation of EC cells dramatically reduces the steady-state levels of KS-FGF mRNA. On the basis of these findings, we hypothesize that the reduction in the production of the FGF-related growth factor that occurs when EC cells differentiate is due to a reduction in the transcription of the KS-FGF gene. To test this hypothesis, five Specific AIMS are proposed: 1) Isolate and sequence a murine cDNA clone for the KS- FGF gene expressed in EC cells, 2) determine the level at which the KS-FGF gene is regulated in EC cells, 3) isolate and sequence the murine gene for KS-FGF, 4) examine non-coding sequences of the KS-FGF gene for possible regulatory function(s), and 5) examine regions of the KS-FGF mRNA for possible post-transcriptional regulatory functions. The work proposed in this application is significant for several reasons. First nad foremost, the mechanisms that repress the expression of an oncogene that is expressed by a wide range of tumor cells and by some Kaposi's sarcoma cells will be examined. Equally important, the proposed work will help address a critical gap in our current knowledge, namely, our limited understanding of the mechanisms by which growth factor production is regulated. In addition, this work will provide a basis for understanding how this oncogene is regulated during early development.