Regulation of the gastrin promoter by epidermal growth factor and neuropeptides.

Abstract

The regulation of gastrin gene transcription was studied in GH4 pituitary cells transfected with constructs comprised of the first exon of the human gastrin gene and various lengths of 5' regulatory sequences ligated upstream of the reporter gene chloramphenicol acetyltransferase. Gastrin reporter gene activity in GH4 cells was equal to the activity of a reporter gene transcribed from the endogenously expressed growth hormone promoter. The effect of a variety of peptides on gastrin gene transcription including epidermal growth factor (normally present in the gastric lumen), gastrinreleasing peptide, vasoactive intestinal peptide, and somatostatin (present in gastric nerves) was assessed. Epidermal growth factor increased the rate of gastrin transcription almost 3-fold, whereas thyrotropin-releasing hormone and vasoactive intestinal peptide increased gastrin transcription 2-and 1.5-fold, respectively. Gastrin-releasing peptide, a peptide that strongly stimulates gastrin release, weakly increased gastrin transcription (1.3-fold). Somatostatin inhibited the increase in gastrin transcription induced by epidermal growth factor, thyrotropin-releasing hormone, and vasoactive intestinal peptide. Constructs containing various lengths of 5' regulatory sequences defmed a response element -40 to -82 base pairs (bp) 5' to the transcription initiation site. This 40-bp sequence contains Spl and AP2 binding sites, which suggests that epidermal growth factor and thyrotropin-releasing hormone stimulate gastrin gene transcription through transcription factors that bind to Spl and/or AP2 motifs.

Treatment ofHelicobactergastritis with IL-4 requires somatostatin

“…These results confirm a critical role for SOM in regulating basal levels of gastrin expression (38). The increase in gastrin in SOM Ϫ/Ϫ mice with Helicobacter infection shows that inflammation is an indepen- dent regulator of gastrin, supporting our prior results (11,27).…”

Apolipoprotein Synthesis in Newborn Piglet Intestinal Explants

“…However, only synthesis of apo A-I and A-IV was affected, and the increase in apolipoprotein synthesis was proportionately greater than that of total explant protein synthesis, because apolipoprotein synthesis, expressed as a percentage of total protein synthesis, significantly increased. The second possibility is a more specific action of EGF on induction of the apo A-I and A-IV genes, possibly though trans-acting transcription regulatory factors, such as has been demonstrated for the increase in transcription of the gastrin gene induced by EGF (50). This mechanism may be further supported by the fact that the apo A-I and A-IV genes are located in a cluster with apo C-111 ( 5 1).…”

Epidermal growth factor induction of human papillomavirus type 16 E6/E7 mRNA in tumour cells involves two AP-1 binding sites in the viral enhancer

“…Interestingly, PK-C can activate the Raf-1 kinase/MAP kinase pathway by direct phosphorylation of Raf-1 (Kolch et al, 1993), suggesting that phorbol esters require the MAP kinase pathway to activate AP-1. In conclusion, AP-1 appears to play a key role in EGF-regulated transcription, although in other systems transcription factors other than AP-1 may allow EGF regulation: the EGF responsive unit of the gastrin promoter does not contain an AP-1 site (Godley & Brand, 1989), and the enhancer from the mouse retrovirus VL30 contains an AP-l-related sequence 5' TGACTCC which does not bind to AP-1 and is not required for the EGF response (Lenormand et al, 1992).…”