Abstract
Unlike p53, which is mutated at a high rate in human cancers, its homologue p73 is not mutated but is often overexpressed, suggesting a possible context-dependent role in growth promotion. Previously, we have shown that co-expression of TAp73 with the proto-oncogene c-Jun can augment cellular growth and potentiate transactivation of activator protein (AP)-1 target genes such as cyclin D1. Here, we provide further mechanistic insights into the cooperative activity between these two transcription factors. Our data show that TAp73-mediated AP-1 target gene transactivation relies on c-Jun dimerization and requires the canonical AP-1 sites on target gene promoters. Interestingly, only selected members of the Fos family of proteins such as c-Fos and Fra1 were found to cooperate with TAp73 in a c-Jun-dependent manner to transactivate AP-1 target promoters. Inducible expression of TAp73 led to the recruitment of these Fos family members to the AP-1 target promoters on which TAp73 was found to be bound near the AP-1 site. Consistent with the binding of TAp73 and AP-1 members on the target promoters in a c-Jun-dependent manner, TAp73 was observed to physically interact with c-Jun specifically at the chromatin via its carboxyl-terminal region. Furthermore, co-expression of c-Fos or Fra1 was able to cooperate with TAp73 in potentiating cellular growth, similarly to c-Jun. These data together suggest that TAp73 plays a vital role in activation of AP-1 target genes via direct binding to c-Jun at the target promoters, leading to enhanced loading of other AP-1 family members, thereby leading to cellular growth.
Highlights
TAp73, which is overexpressed in cancers, activates activator protein (AP)-1 target genes
Co-expression of c-Fos or Fra1 was able to cooperate with TAp73 in potentiating cellular growth, to c-Jun
To gain further mechanistic insights into TAp73-mediated AP-1 activation, we first evaluated the role of the functional domains of c-Jun that are required for cooperation with TAp73. c-Jun deletion mutants that lack the leucine zipper domain that is required for homoand heterodimerization (c-JunDM), the delta domain that is required for docking of Jun N-terminal kinases (c-JunD), or the N-terminal transactivation domain (c-JunTAM67) were used
Summary
TAp73, which is overexpressed in cancers, activates AP-1 target genes. Results: TAp73 binds to c-Jun on the chromatin around TRE sites on AP-1 target promoters, leading to recruitment of other AP-1 family members. We have shown that co-expression of TAp73 with c-Jun stabilizes TAp73 and leads to increased cellular survival via the up-regulation of cyclin D1 at both the RNA and protein levels [26, 33] This up-regulation is dependent on c-Jun and is required for TAp73-induced cell proliferation. Induction of another AP-1 target gene (collagenase/MMP-1) upon treatment with the tumor-promoting phorbol ester (12O-tetradecanoylphorbol-13-acetate) was impaired in p73-null mouse embryonic fibroblasts (MEFs). These data suggested that TAp73 plays a vital role in activation of endogenous AP-1 target genes, thereby contributing to cellular survival. To further understand the details of how TAp73 acts as a growth promoter, we analyzed the mechanistic basis of AP-1 target gene activation by TAp73 and the composition of AP-1 family members involved in this process
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