Endothelin induces transcription of fos/jun family genes: A prominent role for calcium ion

The 21-amino acid mammalian peptide endothelin (ET) is a powerful vasoconstrictor, a mitogen for fibroblasts and vascular smooth muscle cells, and a potent effector for numerous tissues. Through extracellular interaction with G protein-coupled transmembrane receptors, ET stimulates intracellular second messenger events that in turn activate immediate early gene transcription. Using Northern blot hybridization and nuclear run-on analyses we examined the modulation of c-fos, fos-B, fra-1, c-jun, and jun-B gene transcripts in Rat-1 fibroblasts after ET treatment. Furthermore, we invested the role that intracellular Ca²⁺ transients played in effecting this gene regulation, using the intracellular Ca²⁺ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′,-tetraacetic acid (BAPTA) to block Ca²⁺-dependent transcription. Our results demonstrate that ET rapidly effects increased RNA levels for all five fos/jun family genes investigated at least two of them by increasing gene transcription. Furthermore, our results argue that increased intracellular free Ca²⁺ is directly involved in the induction of these fos/jun family genes by ET. While mobilization of intracellular Ca²⁺ is not the only pathway to fos/jun gene induction used by ET, it is clearly a major component of the signaling apparatus that is set in motion by this potent effector.