Proliferative activation of quiescent Rat-1A cells by delta FosB

Fos and Jun transcription factors are induced during the normal course of the proliferative response of quiescent cells to serum or to growth factors. We have shown that delta FosB, an alternatively spliced form of FosB, is formed as rapidly as FosB in serum-stimulated Rat-1A cells. Although delta FosB lacks the C-terminal region of FosB carrying the transactivation function, constitutive expression of delta FosB transforms Rat-1A cells as does expression of FosB. The transforming ability of delta FosB suggests that delta FosB may lead to proliferative activation of quiescent cells without activating AP-1-responsive genes. To address this question, FosB or delta FosB was expressed as a fusion protein with the ligand binding domain of the human estrogen receptor (ER) in Rat-1A cells. After estrogen treatment, the fusion protein accumulates in nuclei and forms stable complexes with Jun proteins. We have shown that ER-delta FosB or to a lesser extent ER-FosB triggers quiescent Rat-1A cells to transit G1, initiate DNA replication, and ultimately undergo cell division at least once. Since ER-FosB, but not ER-delta FosB, induced expression of the AP-1-responsive transin/stromelysin gene, we concluded that the N-terminal region and the DNA binding domain of FosB or delta FosB itself have the potential to regulate cell proliferation and that the transactivation function carried by the C-terminal region of FosB is not essential for the proliferative activation of quiescent cells.