v-Src and EJ Ras alleviate repression of c-Jun by a cell-specific inhibitor

Abstract

The AP-1 family of transcription factors, which includes the proto-oncogene products c-Jun and c-Fos, controls the stimulation of cellular genes by growth factors and the expression of oncogenes, including src and ras. Transcriptional activation by c-Jun is regulated by a cell-type-specific inhibitor that represses the activity of a transcriptional activation domain (A1) of c-Jun by operating through the adjacent negative regulatory region (delta). Here we show that cotransfection of the src or ras oncogene enhances the transcriptional activity of a GAL4:c-Jun hybrid that includes the delta-A1 region of c-Jun, suggesting that the DNA binding and dimerization domain of c-Jun is not required for stimulation by Src or Ras. Moreover, induction of c-Jun activity by Src and Ras occurs in cell lines containing the c-Jun inhibitor but not in a cell line lacking it. The region in c-Jun essential for the stimulatory action of these oncogenes maps to domain A1. These findings suggest the existence of signal-transduction pathways that result in an increase in transcriptional activity of c-Jun and AP-1 by disrupting the c-Jun:inhibitor interaction.

Cell Fate Determination Factor DACH1 Inhibits c-Jun–induced Contact-independent Growth

“…These findings are consistent with the previous studies, in which DACH1 inhibition of AP-1 activity required the DS domain. The activity of Gal4-c-Jun was enhanced by oncogenic Ras, however, deletion of amino acids 1-139 abrogated Ras-induced transactivation ( Figure 9D), consistent with previous findings (Baichwal et al, 1991). DACH1 inhibited c-Jun activation by Ras ( Figure 9E).…”

“…The wild-type and mutant chimeric c-Jun proteins were expressed equally in DACH1-transfected cells ( Figure 8B). Activity of the c-Jun protein was enhanced by oncogenic Ras (Ha-RasV12) consistent with previous findings that Ras alleviates repression of a c-Jun inhibitor (Baichwal et al, 1991). DACH1 expression inhibited c-Jun transactivation by Ha-RasV12 ( Figure 8C).…”

“…Previous studies using in vivo competition assays identified an inhibitor of c-Jun activity (Baichwal and Tjian, 1990;Baichwal et al, 1991). In these prior studies, coexpression of the mammalian expression vector encoding either the wild-type or mutant c-Jun was used to identify the domains of c-Jun required for interaction with the ␦ domain inhibitory factor (Baichwal and Tjian, 1990;Baichwal et al, 1991). In our experiments, the ability of DACH1 to repress activity of c-Jun-E2 was overcome by c-Jun expression in trans ( Figure 10A, lane 3 versus lane 5).…”

“…AP-1 Luc (3TPlux), c-Jun Luc and JunB Luc were described previously (Watanabe et al, 1996). The expression vectors for c-Jun linked to Gal4 or E2 and truncated c-Jun were described previously (Baichwal and Tjian, 1990;Baichwal et al, 1991). The Ha-Ras expression vector was described previously (Albanese et al, 1995).…”

“…The ␦ domain is critical for transcriptional activation by c-Jun. One of the first reported functions of the ␦ domain was its engagement of cell type-specific inhibitors of c-Jun (Bohmann and Tjian, 1989;Baichwal and Tjian, 1990;Baichwal et al, 1991). JNK docks to c-Jun on residues within the ␦ domain (Kallunki et al, 1995(Kallunki et al, , 1996.…”