Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain

Abstract

The tumor suppressor p53 exerts antiproliferation effects through its ability to function as a sequence-specific DNA-binding transcription factor. Here, we demonstrate that p53 can be modified by acetylation both in vivo and in vitro. Remarkably, the site of p53 that is acetylated by its coactivator, p300, resides in a C-terminal domain known to be critical for the regulation of p53 DNA binding. Furthermore, the acetylation of p53 can dramatically stimulate its sequence-specific DNA-binding activity, possibly as a result of an acetylation-induced conformational change. These observations clearly indicate a novel pathway for p53 activation and, importantly, provide an example of an acetylation-mediated change in the function of a nonhistone regulatory protein. These results have significant implications regarding the molecular mechanisms of various acetyltransferase-containing transcriptional coactivators whose primary targets have been presumed to be histones.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…These recent ®ndings suggest that activation of sequence-speci®c DNAbinding by p53 in response to DNA damage may be mediated through CBP/p300 and/or PCAF. Gu and Roeder showed that p300 acetylates the carboxyl terminus of p53 (Gu and Roeder, 1997). Recently Sakaguchi et al showed that PCAF acetylated p53 in vitro on Lys 320 .…”

“…p53 binds strongly to strand breaks by its C-terminal domain (Nelson and and this leads to the stabilization and activation of the protein. Several processes might be implicated in activating p53, including phosphorylation, glycosylation, binding to regulatory proteins, alternative splicing and acetylation (Gu and Roeder, 1997;Siliciano et al, 1997;Giaccia and Kastan, 1998). Perhaps the best studied activator of p53 is DNA damage following ionizing irradiation.…”

“…(**) **p19 ARF is from mouse origin. The human homolog is p14 ARF Regulation of p53 exerted by the C-terminal tail of p53 Modi®cations to the carboxy-terminal, including deletion of the last 30 amino-acids (Hupp et al, 1992), protein-binding (Hupp et al, 1992), phosphorylation of Ser 315 , Ser 318 and Ser 393 Wang and Prives, 1995) and recently acetylation by CREB-binding protein (CBP)/p300 (Gu and Roeder, 1997) were shown to enhance sequencespeci®c DNA-binding of wild-type p53, possibly by inhibition of p53's non-sequence-speci®c DNA-binding activity (Anderson et al, 1997). CBP and p300 are closely related histone acetyl-transferases (HATs) that interact with p53 through its amino terminus and function as coactivators for p53-mediated transcription (Avantaggiati et al, 1997;Lill et al, 1997).…”

p53 protein is activated during muscle differentiation and participates with MyoD in the transcription of muscle creatine kinase gene

“…Moreover, the DNA binding and transcriptional activity of p53 protein increased signi®cantly during di erentiation (Figure 3). The increase in stability and activity of p53 appears to occur simultaneously, and therefore may result from a single change such as phosphorylation or acetylation of the protein Lane, 1994, 1995;Gu and Roeder, 1997). Changes in p53 stability and activity in response to di erent physiological conditions were previously demonstrated.…”

“…A recent study has shown that enhanced phosphorylation of p53 in cells treated with okadaic acid was correlated with an enhanced transcriptional activity of the protein (Lohrum and Scheidtmann, 1996). p53 protein can also be acetylated on its carboxyl-terminal domain (Gu and Roeder, 1997). Acetylation of p53 can dramatically stimulate its sequence-speci®c DNA-binding activity.…”