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Transcription initiation in eukaryotes is a tightly regulated, multi-step process. One important aspect is the interaction of various transcription factors with histone acetyltransferase (HAT) complexes. For example, the HATs p300, CBP and PCAF function as coactivators of the tumor suppressor protein p53, and transcriptional activity of p53 correlates with p53 acetylation by HATs. But p300 and CBP also play roles in promoting beta-catenin-dependent transcription that results in cellular proliferation. Thus, transcription factors with very different roles in the cell require the activity of HAT complexes. The precise mechanisms that define access of transcription factors to HAT complexes have not been defined. As components of HAT complexes, the ADA2 and ADA3 proteins (Alteration/Deficiency in Activation) are likely to play important roles in this process, since yeast and mammalian ADA2 and ADA3 proteins have been shown to function as adaptor or docking proteins for transcription factors. For example, our laboratory’s previous work showed that hADA3 physically interacts with p53 in human cells and is required for full transcriptional activity of p53. We have now established that hADA2 also interacts with p53 through coimmunoprecipitation of over-expressed hADA2 and p53. We demonstrated that coexpressed hADA2 and hADA3 coimmunoprecipitate significantly more p53 than either one alone, indicating that hADA2 and hADA3 may stabilize each other, as well as their interaction with p53. Furthermore, we showed that hADA2 and hADA3 interact with proliferation-inducing beta-catenin by coimmunoprecipitation of over-expressed hADA2, hADA3 and beta-catenin. These results suggest that p53 and beta-catenin (together with the DNA binding proteins LEF or TCF) may have to compete for hADA2 and hADA3 in order to transactivate their target genes. Preliminary results indicate that p53 and beta-catenin indeed interfere with each other in coimmunoprecipitation experiments with hADA2 and hADA3. Additional experiments are currently confirming this finding and are exploring the functional consequences of this competition. The discovery that p53, beta-catenin and, likely, other transcription factors may have to compete for access to HAT complexes by interacting with both hADA2 & hADA3 is intriguing because it provides a novel mechanism by which cell proliferation, differentiation or apoptosis may be regulated. p53 activation through cellular stress may not only lead to activation of p53 target genes, but may simultaneously reduce beta-catenin activity by reducing beta-catenin access to HAT complexes. Likewise, abnormally increased beta-catenin activity in human cancers may blunt the p53 pathway by limiting access of wild-type p53 to HAT complexes.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]