Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion.

The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR.

Fusion proteins of retinoid receptors antagonize TGF-beta-induced growth inhibition of lung epithelial cells.

Transforming growth factor-beta1 (TGF-beta) is a growth factor that has multiple functions including potent inhibition of cell growth. TGF-beta signals by binding to its cell surface serine/threonine kinase receptors, which in turn phosphorylate downstream signal transducers, Smad2 and Smad3. Phosphorylated Smad2 and Smad3, together with Smad4, enter the nucleus and associate with various transcription factors. This complex of transcription factors regulates transcription of a diverse group of genes, leading to growth arrest at G1 phase. Through a functional expression cloning approach, a gag-retinoid X receptor beta (gag-RXRbeta) fusion protein was found to antagonize TGF-beta-induced growth inhibition of mink lung epithelial cells and the fusion between gag and RXRbeta is essential for resistance to the growth inhibition. Like gag-RXRbeta, the oncogenic PLZF-RARalpha fusion protein also antagonizes TGF-beta-induced growth inhibition, and the fusion between PLZF and RARalpha is essential for resistance to TGF-beta. Moreover, TGF-beta and retinoic acid (RA) cooperatively induce growth inhibition as well as transcription of the p15(ink4b) gene, while PLZF-RARalpha represses TGF-beta-induced expression of the p15(ink4b) gene. Together, these results suggest that the TGF-beta and RA pathways cooperate to inhibit cell growth and that PLZF-RARalpha -mediated resistance to TGF-beta may facilitate the development of the PLZF-RARalpha-induced leukemia.