Transforming growth factor-alpha (TGF-alpha), one of the ligands for the epidermal growth factor (EGF) receptor, is expressed in the pituitary gland as well as numerous other tissues. It has been postulated to play a role in the development of pituitary adenomas and cancers in tissues such as breast. TGF-alpha is normally expressed in lactotrophs and this expression is upregulated by estrogen prior to the development of lactotroph hyperplasia. In a transgenic mouse model in which we directed overexpression of TGF alpha to the lactotrophs, lactotroph hyperplasia and adenomata develop. To determine if EGF receptor signaling is required for the pituitary response to pregnancy and estrogen stimulation, we developed a transgenic mouse that expresses a dominant negative EGF receptor in the lactotrophs. The specificity of the growth stimulation to the lactotrophs by the TGF alpha targeted to these cells will be another focus of our investigations. TGF alpha is a general growth factor and the EGF receptor is widely dispersed in the pituitary in cells other than lactotrophs. We therefore propose to investigate how the action of TGF alpha is spatially confined within the pituitary. This question has important implication in development where general growth factor mediate growth responses in specific cell lineages. We propose experiments to test the role of the TGF alpha membrane anchor in the spatial limitation of TGF alpha activity in the pituitary by introducing mutations in the growth factor that either remove the anchor or prevent proteolytic processing. Transgenic mouse models will be created using these mutant TGF alpha precursors. We will also continue our studies of the TGF alpha promoter. We have defined several elements in the TGF alpha promoter which control transcription of this gene in cell cultures. We will extend these studies in transgenic animals to determine the segments of an elements within the TGF alpha promoter that direct expression of the gene to specific tissues such as pituitary, kidney, breast, brain and skin. We will also continue to study the role of p53 in TGF alpha gene expression. We have found that the TGF alpha promoter contains p53 binding sites that confer transcriptional activation upon the TGF alpha gene in response to p53. While a major function of p53 is in tumor suppression, this aspect of p53 function has the paradoxic role of allowing p53 to stimulate cell proliferation in response to DNA damage, thus providing a signal for epithelial repair. We propose to study whether the TGF alpha promoter can be activated by DNA damage in transgenic animals with an intact or knocked-out p53 gene. Together, these studies will test the function of the TGF alpha promoter in vivo.
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