Cooperative actions of p21<scp><sup>WAF</sup></scp><sup>1</sup> and p53 induce Slug protein degradation and suppress cell invasion

Kim, Jong-Doo; Bae, Seunghee; An, Sungkwan; Park, Jong Kuk; Kim, Eun Mi; Hwang, Sang‐Gu; Kim, Wun-Jae; Um, Hong‐Duck

doi:10.15252/embr.201438587

Cited by 59 publications

(47 citation statements)

References 13 publications

(29 reference statements)

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“…p21 can also suppress cell invasion. Notably, we have recently shown that p21 does not simply serve as a downstream mediator of p53 but cooperates with p53 to suppress cell invasion (3). Direct interactions between p53 and p21 were indeed observed, and both proteins were able to bind Mdm2, an E3 ligase, and its substrate Slug, forming a p53/p21/Mdm2/Slug complex that facilitated Mdm2-dependent Slug ubiquitination and degradation.…”

Section: Introductionmentioning

confidence: 93%

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

et al. 2017

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The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-X L to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-X L also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092-100. Ó2017 AACR.

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Section: Introductionmentioning

confidence: 93%

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

et al. 2017

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“…This has been shown to prevent colorectal cancer cell migration and invasion. p53 is able to control the expression of Slug by transcriptional activity-dependent and -independent mechanisms [96,97]. p53 simultaneously promotes the proteasomal degradation of Slug by MDM2, a transcriptional target of p53, while also directly interacting with the MDM2-Slug complex to contribute to Slug degradation [96].…”

Section: The Importance Of Cadherins In Actin Cytoskeleton Remodelingmentioning

confidence: 99%

p53 regulates cytoskeleton remodeling to suppress tumor progression

Araki

Ebata

Guo

et al. 2015

Cell. Mol. Life Sci.

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Cancer cells possess unique characteristics such as invasiveness, the ability to undergo epithelial-mesenchymal transition, and an inherent stemness. Cell morphology is altered during these processes and this is highly dependent on actin cytoskeleton remodeling. Regulation of the actin cytoskeleton is, therefore, important for determination of cell fate. Mutations within the TP53 (tumor suppressor p53) gene leading to loss or gain of function (GOF) of the protein are often observed in aggressive cancer cells. Here, we highlight the roles of p53 and its GOF mutants in cancer cell invasion from the perspective of the actin cytoskeleton; in particular its reorganization and regulation by cell adhesion molecules such as integrins and cadherins. We emphasize the multiple functions of p53 in the regulation of actin cytoskeleton remodeling in response to the extracellular microenvironment, and oncogene activation. Such an approach provides a new perspective in the consideration of novel targets for anti-cancer therapy.

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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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Cooperative actions of p21^WAF¹ and p53 induce Slug protein degradation and suppress cell invasion

Cited by 59 publications

References 13 publications

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

p53 regulates cytoskeleton remodeling to suppress tumor progression

Characterization of cancer-associated missense mutations in MDM2

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Cooperative actions of p21WAF1 and p53 induce Slug protein degradation and suppress cell invasion

Cited by 59 publications

References 13 publications

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

p53 regulates cytoskeleton remodeling to suppress tumor progression

Characterization of cancer-associated missense mutations in MDM2

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Cooperative actions of p21^WAF¹ and p53 induce Slug protein degradation and suppress cell invasion