Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation

The nuclear phosphoprotein c-Jun is a major component of the AP-1 transcrip tion factor, whose activity is augmented by many oncogenes, An important me chanism to stimulate AP-1 function is N-terminal phosphorylation of c-Jun a t the serine residues 63 and 73 by the c-Jun N-terminal kinases (JNKs), Mic e and cells harboring a mutant allele of c-jun, which has the JNK phosphoac ceptor serines changed to alanines (junAA), were used to determine the func tion of c-Jun N-terminal phosphorylation (JNP) during oncogenic transformat ion in vitro and ill ripe. JunAA immortalized fibroblasts expressing v-ras and v-fos showed reduced tumorigenicity in nude mice, but the efficiency of v-src transformation was unaffected by the lack of JNP. To assess the sign ificance of JNP in tumour development in vivo, two transgenic mouse tumour models were employed. Skin tumour development caused by constitutive activa tion of the ras pathway by KS-SOS-P expression and c-fos-induced osteosarco ma formation were impaired in mice lacking JNP. Inhibition of JNP may, ther efore, be a novel therapeutic strategy to inhibit tumour growth in vivo.