SODIUM-BUTYRATE CAUSES AN INCREASE IN THE BLOCK TO TRANSCRIPTIONAL ELONGATION IN THE C-MYC GENE IN SW837 RECTAL-CARCINOMA CELLS

Citation
Dp. Heruth et al., SODIUM-BUTYRATE CAUSES AN INCREASE IN THE BLOCK TO TRANSCRIPTIONAL ELONGATION IN THE C-MYC GENE IN SW837 RECTAL-CARCINOMA CELLS, The Journal of biological chemistry, 268(27), 1993, pp. 20466-20472
Citations number
94
Categorie Soggetti
Biology
ISSN journal
00219258
Volume
268
Issue
27
Year of publication
1993
Pages
20466 - 20472
Database
ISI
SICI code
0021-9258(1993)268:27<20466:SCAIIT>2.0.ZU;2-I
Abstract
Elevated expression of the c-myc oncogene is a frequent finding in tum ors and cell lines derived from carcinomas of the colon and rectum. In a previous study we demonstrated that the differentiation agent sodiu m butyrate causes a rapid reduction in the expression of c-myc RNA in the rectal carcinoma cell line SW837. This effect was blocked by inhib itors of protein synthesis, suggesting that butyrate causes the induct ion of an activity that has a negative effect on c-myc expression In t he present work we demonstrate that the rapid decrease in the level of c-myc RNA, upon treatment of SW837 cells with 2 mM butyrate, is follo wed by a slower decrease in the level of p53 RNA and an increase in th e RNA levels for fibronectin and a placental type alkaline phosphatase . Using in vitro elongation of nascent transcripts to measure transcri ption and actinomycin D chase experiments to measure RNA stability, we show that the reduction in expression of c-myc RNA is due to an incre ase in the block to transcriptional elongation, rather than a decrease in transcriptional initiation or an increase in degradation of the RN A. We conclude that sodium butyrate induces an activity that increases the transcriptional block in SW837 cells, and that regulation of tran scriptional elongation is an important mechanism for regulating c-myc expression in this cell type. A shift in relative usage of the two maj or promoters in the c-myc gene accompanies the reduction in expression . The potential significance of this finding with respect to transcrip tional elongation is discussed. Mutations in the exon 1/intron 1 bound ary region of the c-myc gene cause an increase in transcriptional elon gation in Burkitt lymphoma. We sequenced this region in a series of ce ll lines derived from colorectal carcinomas, all of which had an eleva ted level of c-myc expression, to determine if a similar mutational me chanism is at work in this disease. All of the lines examined had a no rmal c-myc DNA sequence, suggesting that the deregulation of c-myc exp ression in colon cancer is not due to a cis mutation in this region.