Polypeptide growth factors and phorbol ester induce progressive ankylosis (Ank) gene expression in murine and human fibroblasts

Polypeptide growth factors promote cellular proliferation by binding to spe cific plasma membrane-anchored receptors. This interaction triggers the pho sphorylation of signal transducing molecules and the transcriptional activa tion of numerous genes. We have used a differential display approach to ide ntify fibroblast growth factor (FGF)-1-inducible genes in murine NIH 3T3 fi broblasts. Here we report that one of these genes encodes ank, a type IIIa transmembrane protein reported to function in cells as an inorganic pyropho sphate transporter. FGF-1 induction of ank mRNA expression is first detecta ble at 2 h after growth factor addition and is dependent on de novo RNA and protein synthesis. Ank gene expression is also upregulated after treating quiescent fibroblasts with several other mitogenic agents (e.g., calf serum or platelet-derived growth factor-BB) or the tumor promoter phorbol 12-myr istate 13-acetate. Furthermore, in comparison to parental NIH 3T3 cells, on cogene-transformed NIH 3T3 cells constitutively express elevated levels of ank mRNA. FGF-1 also increases ank gene expression in non-immortalized huma n embryonic lung fibroblasts. Finally, the murine and human ank genes are e xpressed in vivo in a tissue-specific manner, with highest levels of mRNA e xpression found in brain, heart, and skeletal muscle. These results indicat e that ank is a growth factor-regulated delayed-early response gene in mamm alian cells, and we propose that increased ank expression during cell cycle progression may be necessary to maintain proper intracellular pyrophosphat e levels during conditions of high cellular metabolic activity. (C) 2001 Wi ley-Liss, Inc.