Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73

Abstract

Recent advances indicate a link between tumour promoters, transformation, and AP-1 activity. Protein kinase C activation increases AP-1 DNA-binding activity independently of new protein synthesis. AP-1 is also stimulated by transforming oncoproteins and growth factors. These proteins are thought to participate in a signalling cascade affecting the nuclear AP-1 complex composed of the Jun and Fos proteins. Because c-Jun is the most potent transactivator in the AP-1 complex and is elevated in Ha-ras-transformed cells, in which c-Fos is downregulated, we focused on it as a potential target. c-Jun could convert input from an oncogenic signalling cascade into changes in gene expression. Indeed, transformation of rat embryo fibroblasts by c-Jun requires an intact transcriptional activation domain and cooperation with oncogenic Ha-ras. Expression of oncogenic Ha-ras augments transactivation by c-Jun and stimulates its phosphorylation. Here we describe the mapping of the Ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-Jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-Jun activity and for cooperation with Ha-ras in ocogenic transformation.

c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

“…Western blot analysis showed that M37 cells have elevated c-Jun protein levels, whereas AJ81 cells have no detectable c-Jun (Figure 3c). c-Jun is phosphorylated by JNK (Jun N-terminal kinase) at serines 63 and 73, which is necessary for its transactivation function (Smeal et al, 1991) but not its coactivation of AR (Wise et al, 1998).…”

Signaling by dual specificity kinases

“…Although it has been observed that functional Rac or CDC42 is required for the activation of JNKK-JNK signaling module, it has been observed that Ras is also involved in the activation JNK signaling pathway (Smeal, 1991, Minden et al, 1994Kyriakis et al, 1994). Recent studies indicate that in the speci®c instances in which Ras is involved in the activation of JNKK/JNK module, it appears that Rac or CDC42 is downstream of Ras mediating the`true' coupling (Coso et al, 1995;Minden et al, 1995).…”

The ras-related GTPase rac1 regulates a proliferative pathway selectively utilized by G-protein coupled receptors

“…The closely related m5 muscarinic receptor also transforms via a ras-dependent pathway (Mattingly et al, 1994). Mutationally activated MEK is su cient for cellular transformation and tumorigenesis (Mansour et al, 1994;Cowley et al, 1994), and Jun is required for transformation by ras (Smeal et al, 1991), thus it is possible that either MAPK or JNK pathways, or both together are utilized to elicit mitogenic responses. The ser/thr kinase raf has been implicated in transformation by m1 receptors (Crespo et al, 1994b), suggesting a MAPK mediated proliferative signal.…”