A number of genes display altered activity in human small cell lung cancer (SCLC), in particular members of the myc family (c-myc, L-myc, N-myc) that frequently are expressed at high levels. GLC4, a cell line established at the State University of Groningen from a SCLC, contains a 30 fold amplified c-myc gene and the cells show a high steady state c-myc transcription rate. The amplified c-myc copies of this cell line are not grossly rearranged and contain the gene's known major EcoRI (12 kb) fragment. To investigate in detail the mechanism(s) responsible for transcriptional activation we analyzed the c-myc promoter region. Whereas point mutations, which often occur in a mutational hot spot region in Burkitt's lymphoma, were not detected, c-myc transcription in GLC4 initiates mainly from P1 instead of the P2 promoter. This promoter shift seems to overcome transcript termination at a transcriptional pause site described for Burkitt's lymphoma c-myc sequence. Our data suggest that the shift of promoter usage - together with gene amplification - plays a likely role in c-myc transcriptional activation in GLC4 SCLC cells.

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