Interplay between TAp73 and selected Activator Protein-1 family members promotes AP-1 target gene activation and cellular growth [Gene Regulation]

May 27th, 2015 by Subramanian, D., Bunjobpol, W., Sabapathy, K.

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 AP-1 target genes such as Cyclin D1. Here, we provide further mechanistic insights into the co-operative activity between these two transcription factors. Our data shows 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 co-operate 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 carboxy-terminal region. Furthermore, co-expression of c-Fos or Fra1 was able to co-operate with TAp73 in potentiating cellular growth, similar to c-Jun. These data together suggests 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.
  • Posted in Journal of Biological Chemistry, Publications
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