SRC- I .Smad3.NF-ATp,BAF60a

N-terminal cbp.P3Q0.hdac.pdcd4.TAF7.JABI.tbp


Stalj bZIP

jnk c-Jun interacting proteins c-Fos.FosB, Fra-i,Fra-2 ATF2.ATF3.B-ATF,JDP1. JDP2,c-Maf, Nrl.PL'.LEts, TFIIB,MyoD, RB.CHOP

Fig.13.1 c-Jun activity is affected by post-translational modification and protein-protein interactions. Protein modification (red lines and yellow boxes) takes place at amino-terminal serines 63 and 73 phosphorylated by JNK; carboxy-terminal threonines 234 and 242, and serine 252 phosphorylated by CKII and GSK-3, whose activities are negatively regulated by the ERK-S6 kinase pathway; sumoylation at lysine 229; acetylation at lysine 271 by p300 and redox-mediated modification of cysteine 272. c-Jun contains two established domains: domain (aa 34-60) and bZIP domain (aa 253-312) (brackets). The domain mediates JNK binding and ubiquitination. A large number of proteins interact with c-Jun bZIP domain, while some are only known to interact with N-terminal, C-terminal, or the full-length of c-Jun.

modification by ubiquitination and sumoylation. While sumoylation targets lysine-229 (Muller et al., 2000), ubiquitination is determined by the cis-acting signal provided in the delta domain (Fig. 13.1). Lacking this domain in v-Jun, allows escape from ubiquitin-dependent degradation and is responsible for the extended stability and longer half-life of v-Jun than c-Jun (Treier et al., 1994). The fact that c-Jun expression is superinduced in the presence of protein synthesis inhibitors suggests that de novo synthesized proteins are involved in its degradation (Lamph et al., 1988).

Induction of c-Jun mRNA by extracellular stimuli is attributed mostly to the activation of its promoter. Besides the binding elements for NF-kB, Spl and CCAAT-binding transcription factors, the c-Jun promoter contains a high-affinity AP-1 binding site that is essential for promoter activation. Site-specific mutagenesis of this binding site prevents induction of c-Jun transcription, suggesting the existence of a positive regulatory loop, in which c-Jun transcription is directly stimulated by its own gene products (Lamph et al., 1988; Angel et al., 1988b; Nakamura et al., 1991). Such autocrine regulation explains how transient TPA treatment or growth factor signals can trigger the prolonged activation of the c-Jun promoter for a biological effect to take place (Angel et al., 1988b). The initiation of the activation loop is independent of de novo protein synthesis; rather it is originated from the pre-existing c-Jun that is activated by signal-induced protein modifications that is most commonly the result of changes in the phosphorylation state of c-Jun (Lamph et al., 1988; Bohmann, 1990; Papavassiliou et al., 1992). Phosphorylation affects c-Jun DNA-binding affinity and modulates the activities of its transcriptional activation domain. In resting cells, c-Jun is phosphorylated on serine and threonine at five sites (Boyle et al., 1991; Baker et al., 1992). Three phosphorylation sites are located just upstream of the basic region in the DNA-binding domain (residues 227-252) and two sites are within the N-terminal transcription activation domain at serines 63 and 73 (Fig. 13.1). When cells are exposed to AP-1 activators, such as TPA, c-Jun undergoes C-terminal domain dephosphorylation that increases in DNA binding activity and a significant increase in N-terminal phosphorylation that enhances its transcriptional activity (Smeal et al., 1991; Smeal et al., 1992; Lin et al., 1992; Nikolakaki et al., 1993). Lack of serine-63 and 73 in Jun B accounts for its irresponsiveness to TPA induced transcriptional activation (Franklin et al., 1992).

Less well-understood modifications are induced by changes of the cellular oxidative status. These changes lead to modulation of the redox state of a conserved cysteine residue in the DNA-binding domains of the Fos and Jun proteins that affect the AP-1 heterodimer DNA binding activity (Fig. 13.1) (Frame et al., 1991; Abate et al., 1990). The redox state of the cell represents the precise balance between the levels of oxidizing and reducing equivalents (Matsuzawa and Ichijo, 2005). Because redox signaling is commonly modulated in response to alterations of both external and internal environments, the resulting c-Jun modification may actually have quite a broad implication in modulation of cell function.

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