The p53 isoforms are differentially modified by Mdm2

Camus, Suzanne; Menéndez, Sergio; Fernandes, Kenneth; Kua, Nelly; Liu, Geng; Xirodimas, Dimitris P.; Lane, David P.; Bourdon, Jean-Christophe

doi:10.4161/cc.20119

Cited by 29 publications

(39 citation statements)

References 50 publications

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“…In addition, it is possible to manipulate p53 isoform expression by regulating their protein-degradation pathway. The entire ubiquitinase network of p53 family proteins is not known yet, but it has been shown that p53 isoforms are differently affected by the main E3 ligase of p53α – MDM2 107. The MDM2 antagonist nutlin-3a has already been shown to be effective in stabilizing p53α to sensitize cells to chemotherapy 101,108.…”

Section: Overview Of the Clinical Implications Of P53 Isoform Activitmentioning

confidence: 99%

Uncovering the role of p53 splice variants in human malignancy: a clinical perspective

Surget¹,

Khoury²,

Bourdon³

2013

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Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets.

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Section: Overview Of the Clinical Implications Of P53 Isoform Activitmentioning

confidence: 99%

Uncovering the role of p53 splice variants in human malignancy: a clinical perspective

Surget¹,

Khoury²,

Bourdon³

2013

OTT

Self Cite

220

140

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“…12,16 We evaluated this possibility by studying the level of global ubiquitination in HDAC inhibitor-treated cells, and then the impact of HR23B on ubiquitination and directly on proteasome activity. We expressed His-tagged ubiquitin in transfected cells and assessed the level of ubiquitin-conjugated proteins by immunoblotting with anti-His antibodies 24 under conditions of drug treatment that causes growth inhibition. 12,16 The global ubiquitination pattern in SAHA-treated (for 20 h) cells was similar to control untreated cells (Figure 2a).…”

Section: Hr23b Influences Autophagymentioning

confidence: 99%

A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors

et al. 2013

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Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment. Cell Death and Differentiation (2013) 20, 1306-1316 doi:10.1038/cdd.2013 published online 24 May 2013 Histone deacetylase is a family of enzymes that control the acetylation of chromatin.1 An increasingly large group of proteins connected with different aspects of normal and tumour cell biology are known to be influenced by acetylation.2-4 As a consequence, the HDAC family has attracted considerable attention as a therapeutic target.2,3,5 Indeed, inhibition of HDAC activity is strongly anti-proliferative on tumour cells in vitro, and delays tumour growth in xenograft models. [5][6][7] An extensive number of clinical trials with HDAC inhibitors in a variety of malignancies are underway, and two HDAC inhibitors, SAHA/Vorinostat and FK228/Romidepsin, have to date been approved for treating a human malignancy, namely cutaneous T-cell lymphoma (CTCL 1,(8)(9)(10) ). However, identifying other malignancies and disease types that are likely to respond favourably to HDAC inhibitors has been hampered, principally because knowledge of the key pathways through which HDAC inhibitors affect tumour cell growth remains limited. 9,11 In previous studies, we undertook through a genome-wide loss-of-function screen to identify genes that have an impact on the sensitivity of tumour cells to HDAC inhibitors. 12 We reasoned that genes identified in this way would not only provide important information on key pathways affected by HDAC inhibitors, but also identify potential biomarkers that inform on the tumour response to HDAC inhibitor-based therapies. 11,12 Through this analysis, we identified HR23B as a protein that influences the response and sensitivity of tumour cells to HDAC inhibitors.12 HR23B functions in at least two pathways; nucleotide excision repair (NER) and protein targeting to the proteasome. [13][14][15] Further studies suggested that the ability of HR23B to engage in proteasomal shuttling underpins its role as a determinant of HDAC inhibitor sensitivity, and it is consistent with this idea that aberrant proteasome activity occurs in tumour cells trea...

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“…We have shown that p53b and p53g proteins are ubiquitinated and degraded by the proteasome. 8 Recently, the serine/arginine-rich (SR) protein SFRS3 has been identified to promote the inclusion of TP53 intron 9b. 9 SR proteins are essential in spliceosome assembly and are specifically and finely regulated by splicingrelated kinases, such as Clk (Cdc2-like kinases) family.…”

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confidence: 99%

Modulation of p53β and p53γ expression by regulating the alternative splicing of TP53 gene modifies cellular response

et al. 2014

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In addition to the tumor suppressor p53 protein, also termed p53a, the TP53 gene produces p53b and p53c through alternative splicing of exons 9b and 9c located within TP53 intron 9. Here we report that both TG003, a specific inhibitor of Cdc2-like kinases (Clk) that regulates the alternative splicing pre-mRNA pathway, and knockdown of SFRS1 increase expression of endogenous p53b and p53c at mRNA and protein levels. Development of a TP53 intron 9 minigene shows that TG003 treatment and knockdown of SFRS1 promote inclusion of TP53 exons 9b/9c. In a series of 85 primary breast tumors, a significant association was observed between expression of SFRS1 and a variant, supporting our experimental data. Using siRNA specifically targeting exons 9b/9c, we demonstrate that cell growth can be driven by modulating p53b and p53c expression in an opposite manner, depending on the cellular context. In MCF7 cells, p53b and p53c promote apoptosis, thus inhibiting cell growth. By transient transfection, we show that p53b enhanced p53a transcriptional activity on the p21 and Bax promoters, while p53c increased p53a transcriptional activity on the Bax promoter only. Moreover, p53b and p53c co-immunoprecipitate with p53a only in the presence of p53-responsive promoter. Interestingly, although p53b and p53c promote apoptosis in MCF7 cells, p53b and p53c maintain cell growth in response to TG003 in a p53a-dependent manner. The dual activities of p53b and p53c isoforms observed in non-treated and TG003-treated cells may result from the impact of TG003 on both expression and activities of p53 isoforms. Overall, our data suggest that p53b and p53c regulate cellular response to modulation of alternative splicing pre-mRNA pathway by a small drug inhibitor. The development of novel drugs targeting alternative splicing process could be used as a novel therapeutic approach in human cancers. including C-terminal isoforms produced by alternative splicing of intron 9 3 (Figure 1a). Exclusion of the entire intron 9 generates the canonical full-length p53 protein (or p53a), a transcription factor activated in response to diverse intracellular and extracellular signals (Figure 1b). Hence, p53 regulates gene expression to modulate cell-fate outcome by regulating biological processes, including apoptosis and cell cycle progression.5 Inclusion of alternative exons 9b and 9g contained in intron 9 gives rise to p53b and p53g protein isoforms that present new residues in place of the usual oligomerization domain present in p53a. Early studies reported that p53b and p53g retain characteristics of a tumor suppressor. 4 Indeed, p53b modulates p53a transcriptional activity in a promoter-dependent manner in response to stress 3 and promotes apoptosis and senescence, indicating that p53b can modulate p53a suppressive activity. 3,6 The biological significance of p53b and p53g isoforms is emphasized by clinical data. Both p53b and p53g expression is lost in B60% of breast cancer tumors.3,7 Furthermore, breast cancer patients expressing both mutant p53 and p53g ha...

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The p53 isoforms are differentially modified by Mdm2

Cited by 29 publications

References 50 publications

Uncovering the role of p53 splice variants in human malignancy: a clinical perspective

Uncovering the role of p53 splice variants in human malignancy: a clinical perspective

A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors

Modulation of p53β and p53γ expression by regulating the alternative splicing of TP53 gene modifies cellular response

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