c-Jun is essential for normal mouse development and hepatogenesis

Abstract

The proto-oncogene c-jun is the cellular homologue of v-jun, the transforming oncogene of the avian sarcoma virus 17 (ref. 1). c-jun encodes one major component of the AP-1 transcription factor complex and is expressed in many organs during mouse development and in the adult. Because of its rapid induction in cells following growth stimulation and the presence of AP-1 binding sites in the promoter regions of many genes, the c-Jun protein is thought to have important functions in cell proliferation and differentiation. But embryonic stem (ES) cells lacking c-Jun are viable and have a normal in vitro differentiation capacity, although c-Jun appears to be important for growth of teratocarcinomas in vivo. To define the function of c-jun better, targeted ES cells were used to generate mice lacking c-Jun. Here we report that heterozygous mutant mice appear normal, but embryos lacking c-Jun die at mid- to late-gestation and exhibit impaired hepatogenesis, altered fetal liver erythropoiesis and generalized oedema. Interestingly, c-jun-/- ES cells can participate efficiently in the development of all somatic cells in chimaeric mice except liver cells, further suggesting an essential function of c-Jun in hepatogenesis.

Diverse functions of JNK signaling and c-Jun in stress response and apoptosis

“…In addition, microinjection of antibodies against c-Jun was shown to inhibit progression of cells from G1 into S phase (Kovary and Bravo, 1991). Studies employing ®broblasts and/or hepatoblasts from c-jun knockout mice demonstrated that c-Jun de®ciency results in a severe proliferation defect, which cannot be compensated by addition of puri®ed mitogens (Eferl et al, 1999;Hilberg et al, 1993;Johnson et al, 1993). Thus, at least in cultured ®broblasts and hepatoblasts, c-Jun acts as a positive regulator of cell growth.…”

“…Mice (Behrens et al, 1999;Erfel et al, 1999;Hilberg et al, 1993;Johnson et al, 1993;Schreiber et al, 1999;Wisdom et al, 1999) c-JunAA Viable As above As above (Behrens et al, 1999) (Ganiatsas et al 1998;Nishina et al, 1996aNishina et al, ,b, 1998Nishina et al, , 1999Yang et al, 1997a) Cellular responses to c-Jun and JNK signaling S Leppa È and D Bohmann lacking the c-Jun phosphorylation sites Ser 63 and 73 show no defects in several forms of normal developmentally regulated apoptosis (Behrens et al, 1999). Even in the complete absence of c-Fos and c-Jun in double knockout mouse embryos, no defects in the normally occurring developmentally programmed cell death were recorded (Ro er-Tarlov et al, 1996).…”

FIP200, a key signaling node to coordinately regulate various cellular processes

“…The liver degeneration phenotype observed in FIP200 KO embryos is similar to the KO embryo phenotypes by deletion of several components in TNFα survival signaling pathways including Rel A, IKK-β, IKK-γ, GSK-3, MKK4, MKK7, or c-Jun, which are characterized by mid/late gestational lethality associated with increased apoptosis in liver [41][42][43][44][45][46][47]. Furthermore, FIP200 KO MEFs exhibit increased apoptosis upon TNFα treatment, which might be explained by the loss of FIP200 interaction with ASK1 and TRAF2, regulation of TRAF2-ASK1 interaction and ASK1 phosphorylation [12].…”

Molecular analysis of Ceruloplasmin in a South African cohort presenting with oesophageal cancer

“…These include the binding motif for activator protein 1 (AP1) which has shown to be involved in cell proliferation, differentiation and tumourigenesis, 44 upstream regulatory factor 1 (USF1) which has defined roles in regulation of genes expressed in the liver 45 and spleen focus forming virus proviral integration oncogene 1 (SPI1) which plays a role in the development of myeloid and b-lymphoid cells which are important during an immune response. 46 The functional importance of these TFs in regulation of CP expression should not be overlooked.…”