Gastrin stimulates expression of protooncogene c-myc through a process involving polyamines in IEC-6 cells.
The current study tested the hypothesis that the protooncogene c-myc is involved in the mechanism by which gastrin modulates mucosal cell proliferation. Studies were conducted in the IEC-6 cell line, derived from rat small intestinal crypt cells. Administration of gastrin resulted in the rapid appearance of c-myc mRNA in IEC-6 cells. The increased expression of c-myc began 1 h and peaked 4 h after exposure to gastrin. Maximum increase in c-myc mRNA levels was 7.5-fold the normal value. When cellular protein synthesis was inhibited by addition of cycloheximide, gastrin superinduced c-myc mRNA levels. Gastrin also significantly increased the mRNA levels for ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis, enzyme activity, and intracellular polyamines in IEC-6 cells. Treatment with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, not only completely depleted intracellular polyamines but also significantly prevented the increased expression of c-myc in cells exposed to gastrin. These results show that 1) gastrin stimulates both polyamine biosynthesis and the expression of the c-myc protooncogene, and 2) depletion of intracellular polyamines by DFMO significantly prevented the increased expression of c-myc by gastrin.
Wang
J Y
JY
Department of Physiology and Biophysics, University of Tennessee College of Medicine, Memphis 38163, USA.
Wang
H
H
Johnson
L R
LR
D000818:Animals; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D005755:Gastrins / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016259:Genes, myc; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology*; D007421:Intestine, Small / Q000166:cytology / Q000502:physiology*; D009955:Ornithine Decarboxylase / Q000235:genetics; D010418:Pentagastrin / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D051381:Rats
D005755:Gastrins; D011073:Polyamines; D003513:Cycloheximide; D009955:Ornithine Decarboxylase; D010418:Pentagastrin