THE CELL-TYPE-SPECIFIC ACTIVATOR REGION OF C-JUN JUXTAPOSES CONSTITUTIVE AND NEGATIVELY REGULATED DOMAINS

Dissection of the cell-type-specific activation region in c-jun reveals two functionally separable regulatory subdomains. One subdomain (a1) functions as a transcriptional activator; adjacent to it is a newly identified domain (epsilon) which, together with the previously defined delta-region, interacts with a cellular factor that modulates the action of a1. Mutants that lack epsilon are constitutively active and do not interact with the cell-type-specific repressor, whereas mutants that have sustained changes in a1 exhibit a reduced trans-activation potential but retain the ability to interact with the repressor. This bipartite and modular organization of the a1/epsilon-domain is further established by demonstrating that a1 can be replaced by the heterologous acidic activator of VP16 and retain proper negative regulation by the cell-specific c-Jun inhibitor along with epsilon and delta. Repression of Jun activity by the inhibitor is not caused by a change in stability, nuclear localization, or DNA-binding activity of the protein. Instead the inhibitor apparently regulates transcriptional activation by interacting directly with delta/epsilon and perhaps masking the a1 domain. These studies suggest that multifunctional activation domains, which are structurally complex, may play an important role in the mechanisms that govern inducible tissue-specific gene expression.