Comparative Binding of p53 to its Promoter and DNA Recognition Elements

Weinberg, Richard L.; Veprintsev, Dmitry B.; Bycroft, Mark; Fersht, Alan R.

doi:10.1016/j.jmb.2005.03.014

Cited by 175 publications

(215 citation statements)

References 52 publications

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“…Acetylation at K120 is indispensable for activation of proapoptotic targets but is not required for activation of growth-arrest targets (16,17). Although the mechanism underlying this target specificity remains to be elucidated, it is possible that acetylation at K120 may impose specificity through altering the p53 quaternary structure and thus endowing p53 binding to low-affinity response elements that are found on proapoptotic promoters (29,30). We also noticed a small amount of cytoplasmic p53-p90 interaction.…”

Section: Discussionmentioning

confidence: 69%

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Dai

Tang

Jung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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p53 functions as a central node for organizing whether the cell responds to stress with apoptosis or cell cycle arrest; however, the molecular events that lead to apoptotic responses are not completely understood. Here, we identified p90 (also called Coiled-Coil Domain Containing 8) as a unique regulator for p53. p90 has no obvious effects on either the levels of p53 or p53-mediated cell cycle arrest but is specifically required for p53-mediated apoptosis upon DNA damage. Notably, p90 is crucial for Tip60-dependent p53 acetylation at Lys120, therefore facilitating activation of the proapoptotic targets. These studies indicate that p90 is a critical cofactor for p53-mediated apoptosis through promoting Tip60-mediated p53 acetylation.T he p53 tumor suppressor acts as the major sensor for a regulatory circuit that monitors signaling pathways from diverse sources, including DNA damage, oncogenic events, and other abnormal cellular processes (1, 2). p53 monitors and responds to a multitude of stress signals by coordinating cell growth arrest or apoptosis (3-5). Central to p53 regulation of these cellular processes is its activity as a transcription factor, although transcription-independent functions of p53 are also critical under some biological settings. The activation of p53 transcription activity requires multiple steps, including sequence-specific DNA binding, antirepression and acquirement of combinations of posttranslational modifications, and recruitment of corepressors/coactivators in a promoter-specific manner (6). To suppress tumor growth, p53 induces either cell growth arrest or apoptosis depending on the cellular context. The molecular mechanisms that govern the choice between growth arrest and apoptosis are extremely important but not well understood (4, 7). As a key player in the stress response, p53 demands an exquisitely complicated network of control and fine-tuning mechanisms to ensure correct, differentiated responses to the various stress signals encountered by cells (2,5,(8)(9)(10).p53 was the first nonhistone protein known to be regulated by acetylation and deacetylation (11,12). There is accumulating evidence indicating that acetylation of p53 plays a major role in activating p53 function during stress responses (2, 13, 14). Following our early findings of C terminus p53 acetylation, we and others recently showed that p53 is also acetylated by Tip60 (also known as KAT5)/MOF (human ortholog of males absent on the first) at residue Lys120 (K120) within the DNA-binding domain (15-17). K120 acetylation is crucial for p53-mediated apoptosis but has no obvious effect on p21 expression, an essential target of p53-mediated growth arrest. Notably, although Tip60 is required for K120 acetylation of p53 in vivo, the levels of K120 acetylation are dynamically regulated in vivo and the interaction between p53 and Tip60 is not very stable, indicating that additional regulators may play a role in controlling K120 acetylation and subsequent p53-mediated apoptotic response (18)(19)(20). Through biochemical pur...

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Section: Discussionmentioning

confidence: 69%

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Dai

Tang

Jung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…This reflects that cell cycle regulatory genes contain more robust p53REs than do proapoptotic genes. 23 The strength of p53-mediated induction of the proapoptotic genes puma, bax, and bak1 correlates with the distance of their respective p53REs from the transcriptional start site, as is the case for many p53 target genes. 24 The puma p53RE is located in the promoter region (À145/À126), those for bax (354/373), and bak1 (596/617, corresponding to BS3) are located in the first intron.…”

Section: Discussionmentioning

confidence: 97%

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

et al. 2011

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During apoptosis Bcl-2 proteins control permeabilization of the mitochondrial outer membrane leading to the release of cytochrome c. Essential gatekeepers for cytochrome c release are the proapoptotic multidomain proteins, Bax, and Bak. The expression of Bax is upregulated upon cellular stress by the tumor suppressor p53. Despite the high functional homology of Bax and Bak, little is known about how the bak gene is regulated. To investigate its transcriptional regulation in further detail, we have analyzed a region spanning 8200 bp upstream of the bak start codon (within exon 2) for transcription factor-binding sites, and identified three p53 consensus sites (BS1-3). Reporter gene assays in combination with site-directed mutagenesis revealed that only one putative p53-binding site (BS3) is necessary and sufficient for induction of reporter gene expression by p53. Consistently, p53 induces expression of endogenous Bak. At the mRNA level, induction of Bak expression is weaker than induction of Puma and p21. Interestingly, Bak expression can also be induced by p73 that binds however to each of the three p53-binding sites within the bak promoter region. Our data suggest that expression of Bak can be induced by both, p53 and p73 utilizing different binding sites within the bak promoter.

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“…It seems that in most cases nature has chosen more flexible sequences to allow the DNA bending required for efficient p53 binding, as was found in the majority of the p53-response elements 33 . Although other sequences such as CTAG also exist, comparative study of the p53 response elements shows that most high-affinity segments contain CATG, while the CTAG containing response elements showed binding affinities at the lower end of the spectrum 17 .…”

Section: Discussionmentioning

confidence: 99%

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Pan

Nussinov

2008

J. Phys. Chem. B

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Specific p53 binding-induced DNA bending and its underlying driving forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome. However, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half site, different DNA bending extents were observed. Our analysis shows that the interactions between p53 dimer-dimer were similar in all complexes; on the other hand, specific interactions between the p53 and DNA, including the interactions of Arg280, Lys120 and Arg248 with the DNA varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence, and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory while those for the CTAG sequence was partially dissociated in part of the trajectory, which affected the stability of nearby Arg280-Gua base interactions. Thus, DNA bending depends on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which in turn are related to the DNA sequence and DNA flexibility.

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Comparative Binding of p53 to its Promoter and DNA Recognition Elements

Cited by 175 publications

References 52 publications

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

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