Intramolecular signal transduction in c-Jun.

Abstract

The DNA‐binding activity of c‐Jun is determined by the phosphorylation state of a cluster of threonine and serine residues located near its COOH‐terminus. We have analyzed the events that lead to c‐Jun activation via dephosphorylation of these sites in response to phorbol esters. Our results indicate that COOH‐terminal dephosphorylation is an indirect consequence of a separate phosphorylation event targeted to the NH2‐terminus of c‐Jun. Thus, the activation of c‐Jun DNA‐binding potential, caused by COOH‐terminal dephosphorylation, may not require the regulation of the kinase/phosphatase system that brings about this change, but rather an alteration in the accessibility of the COOH‐terminal phosphoacceptor sites of c‐Jun.

Role of the ATFa/JNK2 complex in Jun activation

“…The ®rst two threonine residues of each of these motifs (Thr69 and 71 in ATF2, and Thr91 and 93 in c-Jun), which correspond to potential MAP kinase target sites (Marshall, 1995), have been shown to be essential for the transcriptional activity of ATF2 (Gupta et al, 1995;Livingstone et al, 1995) and to contribute to that of c-Jun (Hibi et al, 1993;Derijard et al, 1994;Papavassiliou et al, 1995). To examine the relevance of the corresponding Thr51, 53, 156 and 158 residues to the activity of ATFa, all four residues were converted to alanine, either separately or in combination, and the mutated proteins were assayed for their capacity to activate transcription.…”

“…The JNKs were initially identi®ed by their ability to bind the N-terminus of the c-Jun protein, on a site (now de®ned as the docking site) encompassing amino acids 33 ± 47, and to subsequently phosphorylate the Ser63 and Ser73 residues (Whitmarsh and Davis, 1996;Minden and Karin, 1997). Phosphorylation of these sites stimulates the ability of c-Jun to activate transcription of speci®c target genes by a mechanism which remains largely unknown: it has been proposed, for example, that this phosphorylation may indirectly protect c-Jun from ubiquitinylation, thereby prolonging its half-life (Fuchs et al, 1996(Fuchs et al, , 1997; alternatively, this phosphorylation may induce the dephosphorylation of Thr231, Ser243 and Ser249 residues and, as a consequence, increase cJun DNA-binding activity (Papavassiliou et al, 1995).…”

c-Jun activation is required for 4-hydroxytamoxifen-induced cell death in breast cancer cells

“…To this aim, we performed TUNEL assays in OHT-treated cells ectopically expressing a truncated form of c-Fos (A-Fos), which was shown earlier to efficiently knockdown c-Jun/c-Fos AP-1 heterodimers (Olive et al, 1997). (Papavassiliou et al, 1995;Watson et al, 1998;Dunn et al, 2002). Expression of HA-tagged c-Jun-PanAla protected SkBr3 cells from OHT-induced apoptosis, as only 6% of HA-positive cells were also positive for TUNEL staining, while 58% of HA-negative cells were TUNEL positive (Figures 6i-p).…”

“…JNK induces c-Jun transactivation by phosphorylating the c-Jun N-terminal domain at serines 63/73 and threonines 91/93 (Bannister et al, 1995;Papavassiliou et al, 1995;Morton et al, 2003;Weiss et al, 2003;Nateri et al, 2005;Vinciguerra et al, 2008). By forming stable homodimeric or heterodimeric complexes with Fos or ATF family members, c-Jun constitutes the inducible activator protein-1 (AP-1) transcription factor.…”

Rack1 protects N-terminal phosphorylated c-Jun from Fbw7-mediated degradation

“…The c-Jun oncoprotein is the most prevalent component of the AP-1 transcription factor complex and is tightly regulated by phosphorylation at multiple sites mediated by several kinases. Among these kinases, the c-Jun N-terminal kinases (JNKs) phosphorylate c-Jun at its N-terminus, which promotes c-Jun transcriptional activation (Weiss et al, 2003), DNA-binding activity (Papavassiliou et al, 1995) and protects c-Jun from degradation (Musti et al, 1997). Although c-Jun is known to become more stable after phosphorylation at the N-terminus, the underlying mechanism for the reduced c-Jun ubiquitination and degradation is not known.…”