Regulation of the human sodium-phosphate cotransporter NaP_i-IIb gene promoter by epidermal growth factor

The intestinal sodium-phosphate cotransporter (NaP_i-IIb) plays a major role in intestinal P_i absorption. Epidermal growth factor (EGF) is involved in the regulation of P, homeostasis. However, the role of EGF in intestinal NaP_i-IIb regulation is not clear. The current studies showed that EGF decreased NaP_i-IIb mRNA abundance by 40-50% in both rat intestine and Caco-2 cells. To understand the mechanism of this regulation, we cloned the human NaP_i-IIb gene and promoter region and studied the effect of EGF on NaP_i-IIb gene transcription. The human NaP_i-IIb gene has 12 exons and 11 introns. Two transcription initiation sites were identified by primer extension. Additionally, 2.8 kb of the 5′-flanking region of the gene was characterized as a functional promoter in human intestinal (Caco-2) and human lung (A549) cells. Additional studies showed that EGF inhibited promoter activity by 40-50% in Caco-2 cells and that actinomycin D treatment abolished this inhibition. EGF had no effect on promoter activity in lung (A549) cells. We conclude that the human NaP_i-IIb gene promoter is functional in Caco-2 and A549 cells and that the gene is responsive to EGF by a transcriptionally mediated mechanism in intestinal cells.