Integration of nuclear factor-1 (NF1) into existing signaling pathways leading to growth arrest

We earlier reported the formation of a unique nuclear NF1/Smad complex in serum-restricted fibroblasts that acts as an NF1-dependent repressor of the human adenine nucleotide translocase-2 gene (ANT2). In the present study we show that TGF-β also: a) induces the formation of the repressor complex, b) increases binding of NF1 to the repressor elements (Go elements) in ANT2 and c) inhibits ANT2 expression. Repression of ANT2 by TGF-β is eliminated by mutating the NF1 binding sites in the Go repressor elements. Furthermore, inhibitors of TGF-β RI and MAPK p38 prevent the formation of the NF1/Smad4 repressor complex, the induced binding of NF1 to the Go elements, and the repression of ANT2 mRNA in both serum-restricted and TGF-β-treated cells, suggesting that the same or similar signaling pathways operate under both conditions. The fact that NF1/Smad4 repressor complexes are formed only in growth-inhibited cells implies a novel, but much broader, role for such complexes in the initiation or maintenance of the growth-inhibited state.