T1 IS A C-FOS-RESPONSIVE AND FOSB-RESPONSIVE GENE WHICH IS INDUCED BYGROWTH-FACTORS THROUGH MULTIPLE SIGNAL-TRANSDUCTION PATHWAYS

Stimulation of quiescent cells with growth factors triggers changes in gene expression through multiple signal transduction pathways. One of these changes in Swiss 3T3 cells is the strong accumulation of T1 mRN A which encodes a secreted glycoprotein of the immunoglobulin superfam ily. Proliferating cells continued to express T1 mRNA at a lower level , whereas growth arrest induced either by serum deprivation or by cont act inhibition was paralleled by the disappearance of the T1 mRNA. T1 mRNA synthesis in response to serum and platelet-derived growth factor stimulation is mediated through protein kinase C-dependent and protei n kinase C-independent pathways. Activation of protein kinase A also l ed to T1 gene expression. Ongoing protein synthesis is a prerequisite for TI gene induction by growth factors which defines T1 as a delayed early serum re sponsive gene. The ability of the immediate early trans cription factors c-Fos and FosB to directly induce the T1 gene was dem onstrated in a conditional expression system in the absence of protein synthesis. Furthermore, all known inducers of the T1 gene also lead t o c-fos gene activation. Thus we show that the T1 gene is regulated by signals which are transduced through multiple pathways and provide ev idence that the Fos proteins play an important role in the integration of these pathways.