Essential Roles of E3 Ubiquitin Ligases in p53 Regulation

Sane, Sanam; Rezvani, Khosrow

doi:10.3390/ijms18020442

Cited by 62 publications

(62 citation statements)

References 146 publications

(174 reference statements)

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“…p53 activates transcription of many genes, including those that encode proteins involved in cell-cycle arrest, such as CDK interacting protein 1 (p21 WAF1/CIP1 ), or proapoptotic proteins, such as p53 upregulated modulator of apoptosis (PUMA), NOXA, or FAS (43,44). In unstressed cells, the p53 protein level is low because of proteasomal degradation mainly mediated by MDM2 (34), although other E3s may also be involved (45). However, in response to many stress signals, such as DNA damage, aberrant oncogenic signaling, nutrient deprivation, or hypoxia, p53 accumulates in the nucleus and transactivates numerous target genes.…”

Section: Discussionmentioning

confidence: 99%

SCF(FBXW7)‐mediated degradation of p53 promotes cell recovery after UV‐induced DNA damage

Galindo-Moreno¹,

Giráldez

Limón-Mortés³

et al. 2019

FASEB j.

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Eukaryotic cells have developed sophisticated mechanisms to ensure the integrity of the genome and prevent the transmission of altered genetic information to daughter cells. If this control system fails, accumulation of mutations would increase risk of diseases such as cancer. Ubiquitylation, an essential process for protein degradation and signal transduction, is critical for ensuring genome integrity as well as almost all cellular functions. Here, we investigated the role of the SKP1–Cullin‐1–F‐box protein (SCF)‐[F‐box and tryptophan‐aspartic acid (WD) repeat domain containing 7 (FBXW7)] ubiquitin ligase in cell proliferation by searching for targets implicated in this process. We identified a hitherto‐unknown FBXW7‐interacting protein, p53, which is phosphorylated by glycogen synthase kinase 3 at serine 33 and then ubiquitylated by SCF(FBXW7) and degraded. This ubiquitylation is carried out in normally growing cells but primarily after DNA damage. Specifically, we found that SCF(FBXW7)‐specific targeting of p53 is crucial for the recovery of cell proliferation after UV‐induced DNA damage. Furthermore, we observed that amplification of FBXW7 in wild‐type p53 tumors reduced the survival of patients with breast cancer. These results provide a rationale for using SCF(FBXW7) inhibitors in the treatment of this subset of tumors.—Galindo‐Moreno, M., Giráldez, S., Limón‐Mortés, M. C., Belmonte‐Fernández, A., Reed, S. I., Sáez, C., Japón, M. Á., Tortolero, M., Romero, F. SCF(FBXW7)‐mediated degradation of p53 promotes cell recovery after UV‐induced DNA damage. FASEB J. 33, 11420–11430 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

SCF(FBXW7)‐mediated degradation of p53 promotes cell recovery after UV‐induced DNA damage

Galindo-Moreno¹,

Giráldez

Limón-Mortés³

et al. 2019

FASEB j.

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“…In the previous report, p53 upregulation was also apparent following P5091 addition but persisted much longer in multiple myeloma cells [22]. In HeyA8 cells, p53 and p21 appeared to be labile following P5091-induced increase, suggesting an alternative E3 ligase or degradation pathway rather than the involvement of HDM2 [40, 41]. Considering the fact that HeyA8 and OVCAR-8 harbour wild-type and mutant p53, respectively, it is likely that the increased sensitivity of HeyA8 cells to P5091 may be somewhat attributed to wild-type p53.…”

Section: Discussionmentioning

confidence: 99%

The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status

Wang

Zhang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Ovarian cancer is often diagnosed at later stages with poor prognosis. Recent studies have associated the expression of deubiquitylase USP7 with the survival of ovarian cancers. Being a cysteine protease, USP7 could become a target for pharmacological intervention. Therefore, in this study, we assessed the influence of its inhibitor P5091 on ovarian cancer cells. Methods: Ovarian cancer cells were treated with P5091, and cell proliferation was measured with MTT assay; cell morphology was inspected under a phase-contrast microscope; cell cycle and cell death were examined by flow cytometry. To gain mechanistic insights into its effects, immunoblotting was performed to detect USP7, HDM2, p53, p21, apoptosis and autophagy related proteins. Results: P5091 effectively suppressed the growth of ovarian cancer cells, caused cell cycle blockage, and induced necrosis and apoptosis with more severe phenotypes observed in HeyA8 cells with wild-type p53 than in OVCAR-8 cells with mutant p53. P5091 also prompted autophagy, with more efficient p62 degradation in HeyA8. Conclusion: P5091 shows efficacy in suppressing ovarian cancers harbouring wild-type and mutant p53. Its effects seemed to be enhanced by wild-type p53. The potency of this USP7 inhibitor also correlated with autophagy to some extent. Therefore, the pharmacological targeting of USP7 may serve as a potential therapeutic strategy and warrants further investigation.

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“…For example, E3 ubiquitin ligases dominantly regulate protein levels and activities of the tumor suppressor TP53 and are therefore considered to be a new class of biomarkers and therapeutic targets in diverse types of cancers [19]. …”

Section: Introductionmentioning

confidence: 99%

ρ0 Cells Feature De-Ubiquitination of SLC Transporters and Increased Levels and Fluxes of Amino Acids

Medina

Banaszczak

et al. 2017

IJMS

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Solute carrier (SLC) transporters are a diverse group of membrane transporter proteins that regulate the cellular flux and distribution of endogenous and xenobiotic compounds. Post-translational modifications (PTMs), such as ubiquitination, have recently emerged as one of the major regulatory mechanisms in protein function and localization. Previously, we showed that SLC amino acid transporters were on average 6-fold de-ubiquitinated and increased amino acid levels were detected in ρ0 cells (lacking mitochondrial DNA, mtDNA) compared to parental cells. Here, we elucidated the altered functionality of SLC transporters and their dynamic ubiquitination status by measuring the uptake of several isotopically labeled amino acids in both human osteosarcoma 143B.TK- and ρ0 cells. Our pulse chase analysis indicated that de-ubiquitinated amino acid transporters in ρ0 cells were accompanied by an increased transport rate, which leads to higher levels of amino acids in the cell. Finding SLC transport enhancers is an aim of the pharmaceutical industry in order to compensate for loss of function mutations in these genes. Thus, the ubiquitination status of SLC transporters could be an indicator for their functionality, but evidence for a direct connection between de-ubiquitination and transporter activity has to be further elucidated.

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Essential Roles of E3 Ubiquitin Ligases in p53 Regulation

Cited by 62 publications

References 146 publications

SCF(FBXW7)‐mediated degradation of p53 promotes cell recovery after UV‐induced DNA damage

SCF(FBXW7)‐mediated degradation of p53 promotes cell recovery after UV‐induced DNA damage

The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status

ρ0 Cells Feature De-Ubiquitination of SLC Transporters and Increased Levels and Fluxes of Amino Acids

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