Small bowel adaptation: counterregulatory effects of epidermal growth factor and somatostatin on the program of early gene expression.

BACKGROUND: Small intestinal crypt cell proliferation is essential to the normal renewal of the epithelium, as well as the adaptive responses that follow resection or injury. The present studies were designed to elucidate the molecular mechanisms by which epidermal growth factor (EGF) and somatostatin interact to regulate crypt cell proliferation.
METHODS: Rat crypt (IEC-6) cells were maintained in Dulbecco's modified Eagle's medium plus 10% fetal calf serum and treated with EGF (10 or 100 ng/ml) or somatostatin (0.5 microgram/ml). Cell counts were done to examine the effects on cellular growth, and Northern blot analyses were carried out by using complementary DNA probes corresponding to various protooncogenes.
RESULTS: EGF caused a 41% increase in cellular growth, an effect that was almost completely blocked by pretreatment (30 minutes) with somatostatin. EGF led to dramatic increases in c-fos (greater than 20-fold), c-jun (2-fold), and jun B (3-fold) gene expression at 30 minutes, consistent with the previously characterized immediate-early gene response in IEC-6 cells. Somatostatin alone had no effects on protooncogene levels, but pretreatment with somatostatin resulted in a marked inhibition (80%, p < 0.001 in all cases) of the EGF-induced increases in protooncogene expression.
CONCLUSIONS: Somatostatin inhibits the EGF-induced protooncogene expression in IEC-6 cells. The somatostatin inhibition of immediate-early gene expression lends support to its role as a negative growth regulator in intestinal epithelia and indicates that its effect occur at an upstream site in the cellular growth response.