MDM2–HDAC1-mediated deacetylation of p53 is required for its degradation

Ito, Akihiro; Kawaguchi, Yoshiharu; Lai, Chun-Hsiang; Kovacs, Jeffery; Higashimoto, Yuichiro; Appella, Ettore; Yao, Tso‐Pang

doi:10.1093/emboj/cdf616

Cited by 514 publications

(519 citation statements)

References 32 publications

Supporting

Mentioning

487

Contrasting

Unclassified

Order By: Relevance

“…In this regard, p53 nicely illustrates this phenomenon. As acetylated p53 lysine residues overlap with those that are ubiquitinated, it has been proposed that a major function of p53 acetylation is to promote p53 stability by preventing mdm2-dependent ubiquitination (Ito et al, 2002). On the other hand, some reports have also described an accelerated protein degradation following lysine acetylation (Caron et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

et al. 2006

View full text Add to dashboard Cite

p14 ARF is a tumour suppressor which plays a critical role in p53-dependent or -independent cell growth control. Several studies have recently provided evidence that p14 ARF can also interfere either directly or indirectly with some components of the RB signalling pathway to mediate its antiproliferative activity. The aim of this study was to explore the existence of direct relationships between p14 ARF and RB proteins. We show that p14 ARF promotes the accumulation of a hypoacetylated RB protein, when it is upregulated in a model of stable-inducible clones or physiologically induced following cell exposure to cytotoxic agents. Looking for the mechanisms involved in this process, we demonstrate that the histone acetyl transferase Tip60 directly interacts with RB and stimulates its degradation by the proteasome through acetylation of its C-terminus. Furthermore, and consistent with p14 ARFinduced RB accumulation, we provide evidence that p14 ARF prevents Tip60-mediated RB acetylation, therefore precluding its proteasomal degradation. Overall, our results identify a novel mechanism by which p14 ARF controls the RB pathway to trigger its antiproliferative function.

show abstract

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Strikingly, however, this did not reduce the overall levels of mutant p53 in the Anthracyclines increase mutant p53 levels M Bug and M Dobbelstein presence of doxorubicin (Figure 1e). Of note, doxorubicin treatment did not increase the levels of Mdm2 in U251 cells, in contrast to the wild-type p53-containing U2OS cells (Supplementary Figure S1F); this may explain why acetylation at K382 is of no detectable importance in the accumulation of mutant p53, although acetylation increases the half-life of wild-type p53 (Ito et al, 2002). p53 mRNA and protein levels are augmented in response to doxorubicin treatment, depending on the transcription factors E2F1 and TAp73.…”

Section: Resultsmentioning

confidence: 94%

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Bug

Dobbelstein

2011

Oncogene

View full text Add to dashboard Cite

Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its gain of function. Its accumulation is partially due to enhanced stability, but little is known about how the mRNA levels of mutant p53 can be regulated. Likewise, the impact of cancer therapy on the levels of mutant p53 is poorly understood. We show here that the anthracyclines doxorubicin, daunorubicin and epirubicin further increase the amounts of mutant p53 mRNA and protein in cancer cells. Moreover, we show for the first time that the transcription factor E2F1 associates with the promoter DNA of TP53. Upon genotoxic treatment, E2F1 contributed to the expression of mutant p53, both directly and through induction of TAp73. In contrast, the anthracycline idarubicin and also another topoisomerase inhibitor, etoposide, failed to increase the levels of p53 mRNA, despite their ability to induce the synthesis of TAp73 mRNA. Instead, a natural antisense transcript of TP53, WRAP53, was strongly augmented by idarubicin and etoposide, but only less so by the other anthracyclines under study. RNA corresponding to the first exon of WRAP53 was mainly found in cell nuclei and it reduced the levels of mutant p53. Taken together, this suggests a reciprocal activation pattern of TP53 and WRAP53 by different chemotherapeutics. Reducing the levels of mutant p53 by small-interfering RNA increased chemosensitivity, and idarubicin prevented cell survival more efficiently than the mutant p53-inducing doxorubicin. We conclude that even closely related anthracyclines induce the synthesis of different, opposing transcripts from the TP53 locus. When using these drugs for cancer therapy, the increased levels of mutant p53 may augment its gain of function and thus favor unwanted chemoresistance and tumor progression.

show abstract

“…This dependence appears to vary with the agent used and may be due to differences in potency. Furthermore, acetylation of p53 occurs following HDAC inhibitor administration and may increase its activity and reduce targeting of p53 for degradation [22,39,40]. However, others have shown HDAC inhibitors to have apoptotic effects independent from p53 [41].…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

Jiang

Dowdy

Meng

et al. 2007

Gynecologic Oncology

View full text Add to dashboard Cite

Objective-To characterize the molecular pathways involved in apoptosis following administration of histone deacetylase inhibitors to Type I and II endometrial cancer cells.Methods-Ark2, Ishikawa, and AN3 cell lines representing both Type I and II endometrial cancers were treated with various concentrations of oxamflatin and HDAC inhibitor-1. Cell apoptosis was determined by flow cytometry, nuclear staining, Western blotting, and mitochondrial membrane potential assays.Results-Compared to controls, there was a 95% reduction in the growth of Ark2 cells following administration of histone deacetylase inhibitors and this response was dose-dependent. These agents also caused profound morphologic changes and loss of mitochondrial membrane potentials consistent with the induction of apoptosis. Cleavage of PARP, caspase-9, and caspase-8 was detected, confirming the activation of apoptotic cascades in endometrial carcinoma cells. This effect was present in both serous and endometrioid cell types.Conclusion-Our results suggest that oxamflatin and HDAC inhibitor-1 have potent cytotoxicity in endometrial cancer cells by inducing cell apoptosis. Histone deacetylase inhibitors are promising agents for the treatment of both Type I and II endometrial carcinoma.

show abstract

MDM2–HDAC1-mediated deacetylation of p53 is required for its degradation

Cited by 514 publications

References 32 publications

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

Contact Info

Product

Resources

About