TIP60 Represses Transcriptional Activity of p73β via an MDM2-bridged Ternary Complex

Abstract

TIP60, a histone acetyl transferase, acts as a p53 coactivator by interfering with MDM2-mediated degradation of p53. However, little is known about its functional regulation of p73, which has structural features similar to p53. In this study we found that TIP60 represses apoptosis, which is induced by exogenous and endogenous p73␤. TIP60 also negatively regulated the expression of p73␤ downstream target genes such as p21 and Bax. Moreover, the specific repression of p73␤-mediated transactivation by TIP60 was independent of p53 expression and not due to histone deacetylase recruiting transcriptional machinery. Transcriptional activities of both p73 splicing variants, p73␣ and p73␤, were also repressed by TIP60. Furthermore, TIP60 markedly enhanced p73␤ binding affinity to MDM2 and physically associated with MDM2 through its zinc finger domain, which is specifically localized in the nucleus. Therefore, we demonstrate that TIP60 forms a ternary complex with p73␤, which is directly bridged by MDM2. It is important to note that our findings contribute to a functional linkage between TIP60 and p73␤ through MDM2 in the transcriptional regulation of cellular apoptosis. p73 has significant sequence homology with p53, which provides similar structural features important for transcription factors (1, 2). Both p73 and p53 have an N-terminal transactivation domain, a central DNA binding domain, and a C-terminal oligomerization domain. Although p73 transcriptionally activates certain p53-responsive genes, which are closely related with cell cycle arrest and apoptotic responses (1), there are some functional differences between p73 and p53. For example, some viral oncoproteins including human Papillomavirus E6 and SV40 T-antigen do not interact with p73 even though they bind to p53 to inhibit its transcriptional activity (3, 4). The expression level of p73 is not affected by exposure to DNA-damaging agents such as ultraviolet irradiation, which efficiently increases p53 transcriptional activity (1). Furthermore, p73 was known not only to be necessary for survival and long-term maintenance of central nervous system neurons including postnatal cortical neurons (5) but also to have an anti-apoptotic role during developmental neuron death (6).p73 is specifically activated by post-translational modifications including Chk1 phosphorylation (7), p300/CBP 3 -mediated acetylation (8), and PIAS1 sumoylation (9), which also affects p53 biological activities (10 -12). Transcriptional activation of p73 is repressed by the association of MDM2 with p300/ CBP, which is a transcriptional co-activator of p73 (13). Amphiphysin IIb-1 also inhibits p73 transactivation by sequestering nascent p73 proteins in the cytoplasm (14). Proteasomedependent p73 degradation via ubiquitination is regulated by its interaction with Itch, which does not bind to p53 (15, 16). However, the exact underlying mechanism associated with p73 regulation is not clear.TIP60 (HIV Tat-interacting protein, 60 kDa) was identified as an interaction partner for the HIV-1 Tat prot...

Arsenic trioxide induces apoptosis in NB-4, an acute promyelocytic leukemia cell line, through up-regulation of p73 via suppression of nuclear factor kappa B-mediated inhibition of p73 transcription and prevention of NF-κB-mediated induction of XIAP, cIAP2, BCL-XL and survivin

“…Despite the tumor suppressor activities of p73, only a few types of human tumors have been reported to harbor p73 mutations [27], which implies that other types of molecular mechanisms might be responsible for the deregulation of p73 during oncogenesis. Recently, it has been revealed that sirtuin (SIRT1), a member of sirtuin family of proteins [28], SHP-2 tyrosine phosphatase [29] and TIP60 histone acetyl transferase [30] disrupt p73 transactivation activity that leads to attenuation of p73-mediated apoptosis.…”

Transcriptional Activity of Neural Retina Leucine Zipper (Nrl) Is Regulated by c-Jun N-Terminal Kinase and Tip60 during Retina Development

“…Tip60 associates with transcription factors such as HIV-1 Tat, androgen receptors, and p53 as a coactivator (2,15,24,53,54). In contrast, it is also implicated in the negative regulation of gene expression through binding to STAT3, CREB, and p73 (16,28,60). Moreover, Tip60 mRNA is highly expressed in the early stages of neural retina development (55).…”

The chromodomain-containing histone acetyltransferase TIP60 acts as a code reader, recognizing the epigenetic codes for initiating transcription

“…In other cases, TIP60 directly acetylates the transcription factor, such as p53, to modulate transcriptional activity. 9) On the other hand, TIP60 has also been implicated in the negative regulation of gene expression through its binding to STAT3, 10) cAMP response element-binding protein (CREB), 11) and p73β 12) Despite the increasing number of studies of TIP60, the roles of TIP60 in regulating gene expression from specific promoters are not well understood.…”