Targeting mutant p53 for efficient cancer therapy

Bykov, Vladimir J.N.; Eriksson, Sofi; Bianchi, Julie; Wiman, Klas G.

doi:10.1038/nrc.2017.109

Cited by 737 publications

(592 citation statements)

References 157 publications

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“…It is well known that WT p53 protein is usually maintained at low levels . However, the p53 mutant phenotype leads to abnormal p53 stabilization and mutant p53 protein overexpression . Consistent with this, our study using two independent CRC cohorts suggested that HMGA2 was prognostic among p53‐negative patients who were highly likely to have WT p53 ( TP53 ) genes.…”

Section: Discussionsupporting

confidence: 87%

HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

Wang

et al. 2018

The Journal of Pathology

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High mobility group A2 (HMGA2) is an architectural transcription factor that promotes human colorectal cancer (CRC) aggressiveness by modulating the transcription of target genes. The degradation of p53 is mediated by murine double minute 2 (MDM2) in a proteasome-dependent manner. Here we report that HMGA2 promotes cell cycle progression and inhibits apoptosis in CRC cells in vitro. We also developed an intestinal epithelial cell-specific Hmga2 knock-in (KI) mouse model. It revealed that the Hmga2 KI promoted chemical carcinogen-induced tumorigenesis in the intestine in vivo. In studying the underlying molecular mechanism, we found that HMGA2 formed a protein complex with p53. The tetramerization domain of p53 (amino acids 294-393) and the three AT-hook domains (amino acids 1-83) of HMGA2 were responsible for their direct interaction. We also found that HMGA2 directly bound to MDM2 and the central acidic and zinc finger domains of MDM2 (amino acids 111-360) were required for interaction with HMGA2. Furthermore, our results indicated that HMGA2 promoted MDM2-mediated p53 ubiquitination and degradation. Interestingly, Hmga2 overexpression in Hmga2 KI mice resulted in an increase in the accumulation of ubiquitinated p53. In addition, in two large CRC cohorts, it was demonstrated that high HMGA2 expression was predictive of an adverse outcome in the p53-negative subgroup of CRC patients. In summary, our data have established for the first time a novel mechanism by which HMGA2 functions with p53 and MDM2 to promote CRC progression. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 87%

HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

Wang

et al. 2018

The Journal of Pathology

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“…However, little is known about the function of b3 subunit in tumor. p53 is a cellular stress sensor that triggers transient cell cycle arrest, permanent cell cycle arrest, cellular senescence, and apoptosis [41]. b3 may be a direct target of transcriptional activation by p53 and involved in a proapoptotic pathway through the endoplasmic reticulum in T98G and Saos2 cell lines as described previously [23].…”

Section: Discussionmentioning

confidence: 99%

Voltage‐gated sodium channels β3 subunit promotes tumorigenesis in hepatocellular carcinoma by facilitating p53 degradation

Han

Guo

et al. 2019

FEBS Letters

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The voltage‐gated sodium channels (VGSCs) are aberrantly expressed in a variety of tumors and play an important role in tumor growth and metastasis. Here, we show that VGSCs auxiliary β3 subunit, encoded by the SCN3B gene, promotes proliferation and suppresses apoptosis in HepG2 cells by promoting p53 degradation. β3 significantly increases HepG2 cell proliferation, promotes tumor growth in mouse xenograft models, and suppresses senescence and apoptosis. We found that β3 knockdown stabilizes p53 protein, leading to potentiation of p53‐induced cell cycle arrest, senescence, and apoptosis. Mechanistic studies revealed that β3 could bind to p53, promoting p53 ubiquitination and degradation by stabilizing the p53/MDM2 complex. Our results suggest that β3 is a novel negative regulator of p53 and a potential oncogenic factor.

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“…Tumor suppressor p53 is a crucial coordinator in cellular responses to stress from oncogene activation, DNA damage, and hypoxia [79, 80]. The antiproliferative capability of p53 mediates cell cycle arrest, apoptosis, and even cellular senescence [81, 82].…”

Section: Substrates Of Huwe1mentioning

confidence: 99%

Ubiquitination by HUWE1 in tumorigenesis and beyond

Kao

2018

J Biomed Sci

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Ubiquitination modulates a large repertoire of cellular functions and thus, dysregulation of the ubiquitin system results in multiple human diseases, including cancer. Ubiquitination requires an E3 ligase, which is responsible for substrate recognition and conferring specificity to ubiquitination. HUWE1 is a multifaceted HECT domain-containing ubiquitin E3 ligase, which catalyzes both mono-ubiquitination and K6-, K48- and K63-linked poly-ubiquitination of its substrates. Many of the substrates of HUWE1 play a crucial role in maintaining the homeostasis of cellular development. Not surprisingly, dysregulation of HUWE1 is associated with tumorigenesis and metastasis. HUWE1 is frequently overexpressed in solid tumors, but can be downregulated in brain tumors, suggesting that HUWE1 may possess differing cell-specific functions depending on the downstream targets of HUWE1. This review introduces some important discoveries of the HUWE1 substrates, including those controlling proliferation and differentiation, apoptosis, DNA repair, and responses to stress. In addition, we review the signaling pathways HUWE1 participates in and obstacles to the identification of HUWE1 substrates. We also discuss up-to-date potential therapeutic designs using small molecules or ubiquitin variants (UbV) against the HUWE1 activity. These molecular advances provide a translational platform for future bench-to-bed studies. HUWE1 is a critical ubiquitination modulator during the tumor progression and may serve as a possible therapeutic target for cancer treatment.

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Targeting mutant p53 for efficient cancer therapy

Cited by 737 publications

References 157 publications

HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

Voltage‐gated sodium channels β3 subunit promotes tumorigenesis in hepatocellular carcinoma by facilitating p53 degradation

Ubiquitination by HUWE1 in tumorigenesis and beyond

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