Vasopressin gene expression by non-neuronal cells: Production in the gastrointestinal system and neoplasms of the lung.

摘要

The work described in this thesis was designed to examine the possibility that vasopressin is produced by non-neuronal cells of the gastrointestinal system and the nature and control of vasopressin synthesis by small-cell lung carcinoma. The experimental approach utilized qualitative and quantitative immunocytochemistry, a number of antibodies to the vasopressin precursor, and fixation procedures using both acetone and formaldehyde.;By the criteria of immunohistochemistry, epithelial and other mononuclear cells of the gastrointestinal tract were shown to exhibit a capacity to produce vasopressin gene-products. In some cells, these products related to exons A, B and C of this gene, while in others only those relating to exon C were present. Even in those cells that appeared to express all of the vasopressin gene, an antigenic dependence upon the method of fixation suggested a structural uniqueness of these gene-products. The demonstration that this gastrointestinal synthesis is unaffected by a base deletion in the vasopressin gene shows that it results from expression of a novel gene or that the location has a direct influence on the form of genetic expression. A role for this peptide in gastrointestinal function is suggested by the close association of vasopressin and gastrin synthesis in the antrum, and the location of vasopressin ;Immunohistochemistry revealed that small-cell lung tumors are capable of producing the major components of the vasopressin precursor. However, in a number of these tumors, expression of only exons A and B or exons A and C can be evidenced. The multiple antibody approach adopted in these studies provides strong evidence that all small-cell tumors produce proteins related to the vasopressin gene, and suggests that a combination of these antibodies can be used to image all tumors in patients diagnosed with small-cell lung carcinoma. Quantitative analysis revealed that tumor expression of the gene can be regulated by factors that influence protein kinase activity and by glucocorticoids. Most non-neuroendocrine lung tumors seem to be incapable of synthesizing vasopressin gene-products. For those few exceptional cases, only one of these products, vasopressin-associated human neurophysin, could be demonstrated. This finding is reminiscent of certain duodenal cells that express glycopeptide in the absence of other vasopressin gene-products.;Expression of the vasopressin gene in non-neuronal cells of the gastrointestinal tract and lung neoplasms is similar to that in hypothalamic neurons, because the major gene products formed in the hypothalamus are also present at these peripheral sites. However, differences in the expression of non-neuronal products are suggested by their antigenic characteristics and by the occasional absence of key precursor components.