The Transcriptional Activity of cJun

Transcription initiation requires the assembly of a preinitiation complex, involving a sequential recruitment of the basal transcriptional machinery, TFIIB-TFIID-TFIIA-UpSA complex, co-activators and the RNA polymerase II holoenzymes (Kim et al., 1998; Edelstein et al., 2003). N-terminal phosphorylation of c-Jun at serines 63 and 73 allows it to interact with CREB-binding protein (CBP), a histone acetyltransferase (HAT) known to hyperacetylate N-terminal histone tails to facilitate chromatin opening. Mutation of c-Jun serines 63 and 73 to alanines (Jun 63/73 AA) prevents CBP binding and severely reduces its transcriptional ability (Bannister et al., 1995; Goldman et al., 1997). Other co-activators that act in a similar way are BAF60a, a component of the SWI/SNF chromatin remodeling complex, p300 protein, a homolog of CBP, and steroid receptor coactivator-1 (SRC-1), all of which interact with c-Jun and potentiate AP-1-mediated transactivaton (Fig. 13.1) (Ito et al., 2001; Lee et al., 1996; Lee et al., 1998). These co-activators, however, do not necessarily operate alone and are not mutually exclusive, because SRC-1-stimulated AP-1 activity can be further enhanced by p300 (Lee et al., 1998). Conversely, c-Jun phosphorylation can trigger its dissociation from an inhibitory complex of histone deacetylase 3 (HDAC3), suggesting that c-Jun-mediated transcription activity can also be induced by a de-repression mechanism (Weiss et al., 2003).

The p300 protein, originally cloned by virtue of its interaction with the adenovirus El A protein, causes acetylation not only of histones, but also of c-Jun at Lys271 (Eckner et al., 1994; Vries et al., 2001). By binding to and sequestrating p300 from c-Jun, El A represses API-mediated promoter activity in adenovirus infected cells (Lee et al., 1996; Hagmeyer et al., 1995). Correspondingly, the tumor suppressor PDCD4 suppresses AP-1 activity by binding to c-Jun and preventing its subsequent association with p300 (Bitomsky et al., 2004).

Once the chromatin structure is opened, c-Jun helps recruit the proteins involved in basal transcriptional machinery, of which both TATA-binding protein (TBP) and TBP-associated factors (TAFs), TAF7, bind to the c-Jun N-terminal activation domain, whereas TFIIB binds to the c-Jun bZIP domain (Fig. 13.1) (Franklin et al., 1995; Munz et al., 2003). TAF7 preferentially binds to the DNA-bound and phosphorylated c-Jun, explaining the transcription activation directed only by the activated c-Jun. What likely to happen is that extracellular stimuli-induced signal transduction pathways lead to N-terminal phosphorylation of c-Jun and that only the hyperphosphorylated c-Jun is recognized by co-activators with histone acetyltransferase activity, like p300/CBP, for the task of opening the local chromatin structure. Subsequent interaction of c-Jun with TBP, TAF7 and TFIIB stabilizes the transcription complex and enables more efficient initiation of transcription processes. Such inducible functional interactions with co-factors allow c-Jun to function as a bridge between extracellular signals and the basal transcription machinery to activate specific promoters (Munz et al., 2003).

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