STRUCTURE, EXPRESSION OF PEPTIDE HORMONE GENES IN HUMAN SMALL CELL LUNG CARCINOMA

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Many human small cell lung cancer cells selectively express peptide hormones both in the patient and in tissue culture cell lines derived from biopsy specimens. In patients, these hormones are known to mediate a constellation of endocrine and neurologic symptoms referred to as paraneoplastic syndromes. Two of these peptides, arginine vasopressin (AVP) and gastrin releasing peptide (GRP) are demonstrated mitogens for Swiss 3T3 cells under certain in vitro growth conditions. In addition, monoclonal antisera recognizing the five COOH amino acid residues of the twenty-seven amino acid GRP hormone have been shown to slow the growth of SCLS cells growing in culture and in nude mouse xenografts. Taken together, these results implicate GRP as an autocrine growth regulator of small cell tumors. To better understand the molecular mechanisms governing the selective expression of peptide hormone genes and their biological role in growth regulation, our group is deriving recombinant DNA clones for relevant polyprotein genes and using these clones to detail their gene structure and expression in SCLC. Human AVP Locus Within the last year, we have obtained human genomic clones for AVP and oxytocin (OT) genes an determined their structure and nucleotide sequence. These two structurally similar genes are linked in human genomic DNA, residing within 10 Kb of each other and in opposite transcriptional orientation. The parallels in structure between these two genes strongly suggests that they both evolved from a common ancestral polyprotein gene by duplication and inversion. Despite the similar structure and location of the AVP and OT genes, a human SCLSC cell line (H378) selectively transcribes AVP and not OT. The molecular basis for this selective expression is currently under investigation.