p21WAF1/CIP1 promotes p53 protein degradation by facilitating p53-Wip1 and p53-Mdm2 interaction

Lee, Ji‐Hyun; Kim, Jong-Doo; Kim, Eun Mi; Kim, Ukjin; Kang, Aram; Park, Jong Kuk; Um, Hong‐Duck

doi:10.1016/j.bbrc.2021.01.074

Cited by 12 publications

(9 citation statements)

References 21 publications

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“…We have recently reported that Mdm2 acts more efficiently on p53 in the p53/p21 complex than p53 alone (15). In this regard, our finding that Slug requires p21 for inducing p53 degradation is consistent with the view that Mdm2 mediates Slug-induced p53 degradation.…”

Section: Discussionsupporting

confidence: 90%

“…To address this question, we used HCT116 p21-knockout variant cells. The stability of p53 protein in these variants was much higher than that in HCT116 parental cells, as reported recently (15). Notably, in contrast to HCT116 parental cells, Slug knockdown in p21-knockout cells did not further increase p53 stability (Fig.…”

Section: Slug Reduces P53 Protein Stability In a P21-dependent Mannersupporting

confidence: 81%

“…While Mdm2 ubiquitinates p53 for p53 degradation (10)(11)(12), Mdm2 facilitates the binding of p21 to the proteasome without ubiquitinating p21 (13,14). Our recent studies revealed that Mdm2 binds to p53 in the p53/p21 complex more efficiently than p53 alone (15). Accordingly, the binding of p21 to p53 promoted Mdm2-mediated p53 degradation.…”

Section: Introductionmentioning

confidence: 92%

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Slug promotes p53 and p21 protein degradation by inducing Mdm2 expression in HCT116 colon cancer cells

et al. 2021

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Our previous study revealed that the tumor suppressor/transcription factor p53 directly binds to its transcriptional target, p21, and that the p53/p21 complex binds to zinc finger protein SNAI2 (Slug), a tumor promoter/transcription factor; thereby promoting the degradation of Slug by Mdm2, an E3 ligase. The present study demonstrated that Slug reduced the cellular expression levels of p53 and p21 in HCT116 colon cancer by decreasing their protein stability. In parallel, Slug increased the mRNA and protein expression levels of Mdm2 in these cells. Moreover, knockdown of Mdm2 using specific small interfering RNAs abolished the ability of Slug to induce the degradation of p53 and p21. Considering the well-known function of Mdm2 in facilitating p53 and p21 degradation, these data suggested that Slug promoted p53 and p21 degradation by inducing Mdm2 expression. Moreover, Slug increased ubiquitination levels of p53 in HCT116 cells. This is consistent with the fact that Mdm2 induces p53 degradation by ubiquitinating p53, and further confirmed that Mdm2 acted downstream of Slug. Comparative studies using HCT116 cells and their p53-or p21-knockout variants have revealed that Slug requires p21 to induce p53 degradation. This result is consistent with our previous study, which revealed that Mdm2 acts more efficiently on p53 in the p53/p21 complex compared with on p53 alone. By contrast, Slug did not require p53 to induce p21 degradation, suggesting that p53 was dispensable in Mdm2-mediated p21 degradation. Notably, the ability of Slug to increase/decrease Mdm2/p53 and p21 levels, respectively, was not confined to HCT116 cells alone, but was also confirmed in A549 and H460 lung cancer cells. Collectively, the results of the present study suggested that Slug could counter p53 and p21. The balance between these two opposing groups (Slug vs. p53/p21) may depend on environmental stresses and the internal physiology of cells.

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Section: Discussionsupporting

confidence: 90%

Section: Slug Reduces P53 Protein Stability In a P21-dependent Mannersupporting

confidence: 81%

Section: Introductionmentioning

confidence: 92%

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Slug promotes p53 and p21 protein degradation by inducing Mdm2 expression in HCT116 colon cancer cells

et al. 2021

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“…The activation and inactivation of p53 are precisely regulated by many factors. As shown in Figure 2, the activation of p53 mainly involves biological mechanisms such as acetylation and phosphorylation, while the inactivation of p53 is closely related to its ubiquitination, ubiquitination, and partial dephosphorylation 1,137 . At the same time, various proteins are not only activated by the transcription of p53 but also participate in the regulation of p53 activation or inactivation 138 .…”

Section: Activation and Inactivation Of P53mentioning

confidence: 99%

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

Shen¹,

Wang²,

Mao³

et al. 2023

MedComm

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Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling‐targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor‐promoting role by blocking the mitochondria‐dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.

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“…Second, the MDM2 proteasome itself can act as an E3 ubiquitin ligase that can mediate P53 ubiquitination and degradation, allowing P53 to be maintained at normal physiological low levels (15).MDM2 overexpression can down-regulate P53 activity and promote P53 degradation through the proteasome pathway, which in turn leads to tumor suppressor P53 pathway inactivation, allowing cells to pass through the cell cycle in the presence of DNA damage, which in turn initiates tumorigenesis (16).In addition, MDM2 can regulate cell cycle and apoptosis by interacting with tumor growth suppressors other than P53 (17). P21 is a downstream gene of P53, which encodes a protein that can arrest cell cycle progression and promote apoptosis (18), and MDM2 can promote its degradation by ubiquitinating the marker P21 protein and maintain a low-level state of P21 in the absence of stress signals (19).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-215-5p Promotes Proliferation, Invasion, And Inhibits Apoptosis In Liposarcoma Cells By Targeting MDM2-P53 Signaling Pathways

Song

Bai

Jiang

et al. 2022

Preprint

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Liposarcoma (LPS) is one of the most common soft tissue malignancies in adults, and LPS is characterized by dysregulation of multiple signaling pathways including MDM2 amplification.MicroRNAs (miRNAs) are involved in tumor progression by regulating gene expression through incomplete complementary pairing with the 3 'untranslated region of mRNAs.In this study, we showed that miR-215-5p could target and promote MDM2 expression, and promote LPS cell proliferation, invasion, and inhibit apoptosis.QRT-PCR showed that the expression of MDM2 was significantly higher when miR-215-5p was overexpressed (2.85 ± 0.48), and dual-luciferase reporter gene showed that the fluorescence intensity ratio decreased in the overexpression group (0.72 ± 0.02), and cell phenotype assay revealed that the proliferation activity increased in the overexpression group, with cell proliferation rates of 104 ± 0.04 (%), 116 ± 0.01 (%), and 120 ± 0.01 (%), increased apoptosis rate (1.47 ± 0.33 (%)), increased colony formation rate (85.10 ± 2.85 (%)), increased cell healing area ratio (30.08 ± 2.00 (%)), and increased cell invasion number (138 ± 3.60) at 24 h, 48 h, and 72 h, respectively; FISH revealed that miR-215-5p colocalized with MDM2, and MDM2 expression increased in the overexpression group, WB suggested that Bax expression decreased, PCNA, Bcl-2, and MDM2 expression increased, and P53 and p21 expression decreased in the overexpression group;These data suggest that miR-215-5p can promote LPS progression through the MDM2-P53 signaling pathway, and targeting miR-215-5p may be a novel therapeutic strategy for the treatment of LPS.

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p21WAF1/CIP1 promotes p53 protein degradation by facilitating p53-Wip1 and p53-Mdm2 interaction

Cited by 12 publications

References 21 publications

Slug promotes p53 and p21 protein degradation by inducing Mdm2 expression in HCT116 colon cancer cells

Slug promotes p53 and p21 protein degradation by inducing Mdm2 expression in HCT116 colon cancer cells

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

MicroRNA-215-5p Promotes Proliferation, Invasion, And Inhibits Apoptosis In Liposarcoma Cells By Targeting MDM2-P53 Signaling Pathways

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