p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug

Wang, Shu Ping; Wang, Wen Lung; Chang, Yih‐Leong; Wu, Chen; Chao, Yu Chih; Kao, Shu Huei; Yuan, Ang; Lin, Chung-Wu; Yang, Shuenn Chen; Chan, Wing Kai; Li, Ker Chau; Hong, Tse-Ming; Yang, Pan Chyr

doi:10.1038/ncb1875

Cited by 432 publications

(393 citation statements)

References 41 publications

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“…As a consequence, the cells may become more resistant to further cycles of genotoxic therapy (Blandino et al, 1999;Bush and Li, 2002). Mutant p53 gain of function would also include cell spread, invasion and metastasis (Heinlein et al, 2008;Adorno et al, 2009;Muller et al, 2009;Wang et al, 2009). Although difficult to prove, the possibility of enhanced tumor progression should be taken into consideration.…”

Section: Potential Consequences For Tumor Progressionmentioning

confidence: 99%

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

Bug

Dobbelstein

2011

Oncogene

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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.

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Section: Potential Consequences For Tumor Progressionmentioning

confidence: 99%

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

Bug

Dobbelstein

2011

Oncogene

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“…Although we find that RAS activation can clearly induce Snail2 expression in a given cell system, there is no evidence of a general correlation between RAS mutational status and Snail2 expression levels in tumours and cancer cell lines. This is likely due to the complexity of the regulation of Snail2 expression, with several pathways contributing to its control, including TGF-b, Wnt and p53 (Wu et al, 2005;Cobaleda et al, 2007;Peinado et al, 2007;Wang et al, 2009). It is well established that activation of RAS in epithelial cells can cooperate with other pathways, such as TGF-b, to lead to EMT (Oft et al, 1996;Lehmann et al, 2000;Huber et al, 2005;Larue and Bellacosa, 2005;Thiery and Sleeman, 2006).…”

Section: Snail2 In Ras Induced Emtmentioning

confidence: 99%

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

et al. 2010

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Activating mutations in the KRAS gene are among the most prevalent genetic changes in human cancers. To identify synthetic lethal interactions in cancer cells harbouring mutant KRAS, we performed a large-scale screen in isogenic paired colon cancer cell lines that differ by a single allele of mutant KRAS using an inducible short hairpin RNA interference library. Snail2, a zinc finger transcriptional repressor encoded by the SNAI2 gene, was found to be selectively required for the long-term survival of cancer cells with mutant KRAS that have undergone epithelial-mesenchymal transition (EMT), a transdifferentiation event that is frequently seen in advanced tumours and is promoted by RAS activation. Snail2 expression is regulated by the RAS pathway and is required for EMT. Our findings support Snail2 as a possible target for the treatment of the broad spectrum of human cancers of epithelial origin with mutant RAS that have undergone EMT and are characterized by a high degree of chemoresistance and radioresistance.

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“…Although p53 is considered the primary target of MDM2, there are other substrates for this E3-ligase; for example, MDM2 has been shown to promote the degradation of human telomerase reverse transcriptase (hTERT), PCNA, Notch4, and Slug. [39][40][41][42][43] For 2 of these substrates, Notch4 and Slug, p53 has been reported to be part of a trimeric complex (i.e., Notch4-MDM2-p53 or Slug-MDM2-p53), in which p53 plays a key role in regulating their degradation. [41][42][43] Thus, mutations that abrogate the interaction between p53 and MDM2 could presumably disrupt the formation of these trimeric complexes, resulting in the stabilization of Notch4 and Slug.…”

Section: Discussionmentioning

confidence: 99%

“…[39][40][41][42][43] For 2 of these substrates, Notch4 and Slug, p53 has been reported to be part of a trimeric complex (i.e., Notch4-MDM2-p53 or Slug-MDM2-p53), in which p53 plays a key role in regulating their degradation. [41][42][43] Thus, mutations that abrogate the interaction between p53 and MDM2 could presumably disrupt the formation of these trimeric complexes, resulting in the stabilization of Notch4 and Slug. In a similar manner, mutations in the MDM2 RING domain that disable its ubiquitin ligase activity would retain the capacity to form a trimeric complex between p53 and either Notch4 or Slug, but would be unable to promote their degradation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of cancer-associated missense mutations in MDM2

Chauhan

Gopalakrishnan

Kollareddy

et al. 2015

Molecular & Cellular Oncology

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MDM2 is an E3 ubiquitin ligase that binds the N-terminus of p53 and promotes its ubiquitin-dependent degradation. Elevated levels of MDM2 due to overexpression or gene amplification can contribute to tumor development by suppressing p53 activity. Since MDM2 is an oncogene, we explored the possibility that other genetic lesions, namely missense mutations, might alter its activities. We selected mutations in MDM2 that reside in one of the 4 key regions of the protein: p53 binding domain, acidic domain, zinc finger domain, and the RING domain. Unexpectedly, we observed that individual mutations in several of these domains compromised the ability of MDM2 to degrade p53. Mutations in the N-terminal p53 binding domain prevented the formation of a p53-MDM2 complex, thereby protecting p53 from degradation. Additionally, as would be predicted, several cancer-associated mutations in the RING finger domain disrupted the ubiquitin ligase activity of MDM2 and prevented p53 degradation. Interestingly, we observed that amino acid substitutions at the same codon differentially affected MDM2 activity. Our data reveal that mutations in this oncogene can have the paradoxical effect of suppressing its activity. Further understanding of how these mutations perturb MDM2 function may yield novel approaches to inhibiting its activity.

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p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug

Cited by 432 publications

References 41 publications

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

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

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

Characterization of cancer-associated missense mutations in MDM2

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