FUNCTIONAL-ANALYSIS OF THE HUMAN PROOPIOMELANOCORTIN PROMOTER IN THE SMALL-CELL LUNG-CARCINOMA CELL-LINE DMS-79

DMS-79 is a human cell line derived from a small cell lung carcinoma ( SCLC), which expresses the pro-opiomelanocortin (POMC) gene. We took i t as a model in which to study the mechanism of POMC gene expression i n non-pituitary tumours. DMS-79 reproduces the usual characteristics o f POMC expression in these tumours: precursor processing is altered an d gene expression is essentially unresponsive to glucocorticoids. POMC gene structure appeared normal by Southern blot analysis, indicating that gene rearrangement was not responsible for its expression in DMS- 79. Indeed, using transient expression of human POMC-luciferase fusion genes in DMS-79, we showed that (1) the normal human POMC promoter wa s functional in DMS-79, and (2) the same proximal promoter region (-41 7;+21) produced the full transcriptional activity in DMS-79 and in the mouse pituitary cell line AtT-20. Progressive 5' deletion analysis re vealed differences between AtT-20 and DMS-79: region (-161;-376) was a ctive in AtT-20 and not in DMS-79, whereas region (-95; -161) was acti ve in both cell lines and (-376; -417) was only active in DMS-79. The latter partially overlaps a motif homologous to the DE-2 rat element w hich confers the tissue-specific expression of POMC in AtT-20 cells; h owever, this motif had no effect in DMS-79. These data suggest that PO MC gene transcription is achieved through a different set of transacti ng factors in DMS-79 and AtT-20. Altogether, our results provide evide nce that DMS-79 is a valid model of tumours responsible for the ectopi c ACTH syndrome and mechanism POMC gene expression SCLC cells differen t from that in pituitary cells.