Hyperacetylation of the C-terminal domain of p53 inhibits the formation of the p53/p21 complex

Kim, Ukjin; Kim, Kwang Seok; Park, Jongkuk; Um, Hong‐Duck

doi:10.1016/j.bbrc.2022.10.037

Cited by 3 publications

(4 citation statements)

References 20 publications

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“…Previous reports indicate that p53 has three major NEDDylation sites, including K370, K372, and K373. Moreover, K373 of p53 could also be modified by multiple PTMs, including ubiquitination and acetylation 36,38 . Through Western blot analysis, we observed that co‐overexpression of UBE1C and NEDD8 decreased the acetylation level of p53 at K373, while the acetylation level at K382 residue 47 remains unchanged (Figure 3A).…”

Section: Resultsmentioning

confidence: 97%

“…Moreover, K373 of p53 could also be modified by multiple PTMs, including ubiquitination and acetylation. 36,38 Through Western blot analysis, we observed that co-overexpression of UBE1C and NEDD8 decreased the acetylation level of p53 at K373, while the acetylation level at K382 residue 47 remains unchanged (Figure 3A). These findings suggest that the decreased transcriptional activity of p53 predominantly occurs at the K373 residue.…”

Section: Neddylation Of P53 Inhibits Its K373 Acetylation and Decreas...mentioning

confidence: 99%

“…[31][32][33][34][35] In response to cellular stresses, multiple lysine residues on the C-terminal regulatory domain could be modified by various PTMs, including phosphorylation, ubiquitination, sumoylation, NEDDylation, and acetylation. [36][37][38][39] For example, the K370, K372, and K373 of p53 C-terminal domain are the main sites for NEDD8 conjugation, regulated by MDM2 and FBXO11 through their activity as ubiquitin E3 ligases. [40][41][42][43] NEDDylated p53 has been reported to be localized mainly in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

“…p53 protein is composed of four functional domains and serves as an important transcriptional factor for many genes 31–35 . In response to cellular stresses, multiple lysine residues on the C‐terminal regulatory domain could be modified by various PTMs, including phosphorylation, ubiquitination, sumoylation, NEDDylation, and acetylation 36–39 . For example, the K370, K372, and K373 of p53 C‐terminal domain are the main sites for NEDD8 conjugation, regulated by MDM2 and FBXO11 through their activity as ubiquitin E3 ligases 40–43 .…”

Section: Introductionmentioning

confidence: 99%

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UBE1C is upregulated and promotes neddylation of p53 in lung cancer

Liu,

Shih,

Wang

et al. 2023

The FASEB Journal

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NEDDylation is a type of protein post‐translational modification that has high similarity to ubiquitination. UBE1C encodes NEDDylation E1 enzyme, locates at chromatin region 3p14.1 and shows high gene dosage amplification frequency in both Asian and Caucasian lung cancer patients. However, its NEDDylation substrates and roles in tumorigenesis remain elucidated. In this study, we aim to investigate the oncogenic role of UBE1C and its involvement in how NEDDylation regulates p53 in lung cancer. We found that UBE1C mRNA overexpression and DNA amplification in most of the lung cell lines and cancer patients. Patients with UBE1C overexpression showed poor prognosis. Moreover, we demonstrated that overexpression of UBE1C and NEDD8, a NEDDylation moiety, resulted in the p53 NEDDylation with inhibition of p53 acetylation at K373 residue. Importantly, UBE1C‐mediated NEDDylation downregulated the transcriptional activity of p53 by inhibiting p53 ability to target promoter regions of its downstream transcription targets, consequently inhibiting the promoter activities and the expression of mRNA and protein of the p53 downstream genes including p21 and PTEN. In addition, UBE1C and NEDD8 overexpression promoted migration, invasion, and proliferation of lung cancer cells. Our findings suggest that UBE1C acts as an oncogene with prognostic potential and highlight a potential role of UBE1C‐mediated NEDDylation in downregulation of p53 transcriptional activity in lung cancer.

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Section: Resultsmentioning

confidence: 97%

Section: Neddylation Of P53 Inhibits Its K373 Acetylation and Decreas...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

UBE1C is upregulated and promotes neddylation of p53 in lung cancer

Liu,

Shih,

Wang

et al. 2023

The FASEB Journal

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Therapeutic potential of natural molecules against Alzheimer's disease via SIRT1 modulation

Zhang¹,

Tang²

2023

Biomedicine & Pharmacotherapy

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Why Is Longevity Still a Scientific Mystery? Sirtuins—Past, Present and Future

Ziętara

Dziewięcka

Augustyniak

2022

IJMS

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The sirtuin system consists of seven highly conserved regulatory enzymes responsible for metabolism, antioxidant protection, and cell cycle regulation. The great interest in sirtuins is associated with the potential impact on life extension. This article summarizes the latest research on the activity of sirtuins and their role in the aging process. The effects of compounds that modulate the activity of sirtuins were discussed, and in numerous studies, their effectiveness was demonstrated. Attention was paid to the role of a caloric restriction and the risks associated with the influence of careless sirtuin modulation on the organism. It has been shown that low modulators’ bioavailability/retention time is a crucial problem for optimal regulation of the studied pathways. Therefore, a detailed understanding of the modulator structure and potential reactivity with sirtuins in silico studies should precede in vitro and in vivo experiments. The latest achievements in nanobiotechnology make it possible to create promising molecules, but many of them remain in the sphere of plans and concepts. It seems that solving the mystery of longevity will have to wait for new scientific discoveries.

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Hyperacetylation of the C-terminal domain of p53 inhibits the formation of the p53/p21 complex

Cited by 3 publications

References 20 publications

UBE1C is upregulated and promotes neddylation of p53 in lung cancer

UBE1C is upregulated and promotes neddylation of p53 in lung cancer

Therapeutic potential of natural molecules against Alzheimer's disease via SIRT1 modulation

Why Is Longevity Still a Scientific Mystery? Sirtuins—Past, Present and Future

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