Abstract 215: Mechanisms of p53 activation by NIAM, nuclear interactor of ARF and MDM2

Nuclear interactor of ARF and Mdm2, NIAM, is a novel regulator of the ARF-Mdm2-p53 tumor suppressor pathway. It collaborates with ARF, promotes p53 transcriptional activity, and is negatively regulated by Mdm2-mediated ubiquitination and proteasome degradation. How NIAM activates p53 is not known, however its ability to do so in ARF-null cells reveals it is an ARF-independent process. Our preliminary data suggest that NIAM could activate p53 by either competing Mdm2 away from p53-Mdm2 complexes and/or by inducing lysine 120 acetylation of p53 via the Tip60 acetyltransferase. p53 acetylation at K120 is known to be regulated by two different histone acetyltransferases, Tip60 and MOF, and to promote the specific upregulation of apoptotic genes by p53. Our preliminary data show that NIAM interacts with Tip60 and strongly promotes p53 acetylation of K120, suggesting a functional NIAM-Tip60 interaction in vivo. Tip60 is an established chromatin modifying protein that influences chromatin structure and cancer gene expression. Consistent with these characteristics of Tip60, we discovered that NIAM is a chromatin-associated protein that binds to transcriptionally active regions of the genome. Other findings connect Tip60 and NIAM. Tip60 acts through p53, ARF and Myc to control transcription and promote the DNA damage checkpoint response. We found that NIAM, like Tip60, localizes to sites of DNA repair in response to DNA damage and it is already established that the absence of either protein leads to chromosomal instability. These compelling observations link NIAM with chromatin regulation and DNA damage repair, potentially via Tip60 signaling, all of which are important for the maintenance of chromosomal stability and prevention of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 215. doi:1538-7445.AM2012-215