Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosisand cellular proliferation

c-Jun is a major component of the heterodimeric transcription factor AP-1 a nd is essential for embryonic development, as fetuses lacking Jun die at mi d-gestation(1,2) with impaired hepatogenesis(1) and primary Jun(-/-) fibrob lasts have a severe proliferation defect and undergo premature senescence i n vitro(2). c-Jun and AP-1 activities are regulated by E-Jun N-terminal pho sphorylation (JNP) at serines 63 and 73 through Jun N-terminal kinases(3,4) (JNKs). INP is thought to be required for the anti-apoptotic function of c -Jun during hepatogenesis, as mice lacking the JNK kinase SEK1 exhibit rive r defects similar to those seen in Jun(-/-) fetuses(5). To investigate the physiological relevance of JNP, we replaced endogenous Jun by a mutant Jun allele with serines 63 and 73 mutated to alanines (Jun(tm1Wag-); hereafter referred to as JunAA). Here we show that primary JunAA fibroblasts have pro liferation- and stress-induced apoptotic defects, accompanied by reduced AP -1 activity. JunAA mice are viable and fertile, smaller than controls and r esistant to epileptic seizures and neuronal apoptosis induced by the excita tory amino acid kainate. Primary mutant neurons are also protected from apo ptosis and exhibit unaltered JNK activity. Our results provide evidence tha t JNP is dispensable for mouse development, and identify c-Jun as the essen tial substrate of INK signalling during kainate-induced neuronal apoptosis.