Discriminative SKP2 Interactions with CDK-Cyclin Complexes Support a Cyclin A-Specific Role in p27KIP1 Degradation

Salamina, Marco; Montefiore, Bailey C.; Liu, Mengxi; Wood, D.J.; Heath, Richard A.; Ault, James R.; Wang, Lan-Zhen; Korolchuk, S.; Baslé, Arnaud; Pastok, Martyna W.; Reeks, Judith; Tatum, Natalie J.; Sobott, Frank; Arold, Stefan T.; Pagano, Michele; Noble, M.E.M.; Endicott, J.A.

doi:10.1016/j.jmb.2020.166795

Cited by 13 publications

(13 citation statements)

References 60 publications

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“…Targeting SCF E3 ubiquitin ligases have been identified as a promising strategy for developing anticancer drugs. [37,38] Skp2, an F-box protein in the SCF complex, specifically recognizes p27, [39] and Skp2 expression is inversely correlated with p27 expression in many types of cancers. [37] Accumulative evidence has demonstrated that Skp2-targeted drugs can directly induce p27 accumulation and G1 phase cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

Ethanol Extract of Citrus grandis ‘Tomentosa’ Exerts Anticancer Effects by Targeting Skp2/p27 Pathway in Non‐Small Cell Lung Cancer

Huang

Chen

et al. 2023

Molecular Nutrition Food Res

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ScopeThis study aims to investigate the anticancer properties of Citrus grandis ‘Tomentosa’ (CGT) in non‐small cell lung cancer (NSCLC).Methods and resultsThe ethanol extract of CGT (CGTE) is prepared by using anhydrous ethanol and analyzed by ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS), revealing that the main chemical components in CGTE are flavonoids and coumarins, such as naringin, rhoifolin, apigenin, bergaptol, and osthole. CGTE at concentrations without inducing cell death significantly inhibits cell proliferation via inducing cell cycle G1 phase arrest by MTT, colony formation, and flow cytometry assays, implying that CGT has anticancer potential. CGTE markedly inhibits the activity of Skp2‐SCF E3 ubiquitin ligase, decreases the protein level of Skp2, and promotes the accumulation of p27 by co‐immunoprecipitation (co‐IP) and in vivo ubiquitination assay; whereas Skp2 overexpression rescues the effects of CGTE in NSCLC cells. In subcutaneous LLC allograft and A549 xenograft mouse models, CGTE, without causing obvious side effects in mice, significantly inhibits lung tumor growth by targeting the Skp2/p27 signaling pathway.ConclusionThese findings demonstrate that CGTE efficiently inhibits NSCLC proliferation both in vitro and in vivo by targeting the Skp2/p27 signaling pathway, suggesting that CGTE may serve as a therapeutic candidate for NSCLC treatment.

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Section: Discussionmentioning

confidence: 99%

Ethanol Extract of Citrus grandis ‘Tomentosa’ Exerts Anticancer Effects by Targeting Skp2/p27 Pathway in Non‐Small Cell Lung Cancer

Huang

Chen

et al. 2023

Molecular Nutrition Food Res

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“…95 Characterisation of the binding of SKP2 (S-phase kinase associated protein) to cyclin A has revealed how cyclin recruitment site promiscuity for binding SLiMs is increased by being able to recognise sequences in a ''reverse'' binding mode 96 and how mutations can both dial up and down affinity for competing proteins, in this example SKP2 vs. p27. 97 Cyclin B has provided the first example of a SLiM binding site on the C-terminal CBF (C-CBF) surface of a cell cycle cyclin. CDK1-cyclin B is the master mitotic regulator and phosphorylates many mitotic proteins to effect substantial cellular reorganisation to facilitate chromatid segregation and cytokinesis.…”

Section: Cdk-containing Macromolecular Complexesmentioning

confidence: 99%

Section: Cdk-containing Macromolecular Complexesmentioning

confidence: 99%

Emerging approaches to CDK inhibitor development, a structural perspective

2023

Self Cite

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“…S-phase kinase-associated protein 2 (Skp2) acts as an E3 ligase, and its Fbox domain can form SCF (skp1-cullin-F-box) complex with Skp1, Cullin1, and Rbx1 [ 7 ]. Skp2, as the E3 ligase of the SCF complex, regulates important cellular biological processes by recognizing substrates for ubiquitination and then degrades phosphorylated P27 Kip1 via protein-ubiquitin pathway or enhances interactions with other proteins and regulates protein activity, such as cell cycle, DNA repair, Akt activation, and mitosis [ 8 , 9 ]. For example, the SCF-Skp2 complex regulates the cell cycle by inhibiting degradation of p21 Cip1/Waf1 and p27 Kip1 by ubiquitin-mediated cyclin-dependent kinase (CDK) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

miR-590-5p Targets Skp2 to Inhibit the Growth and Invasion of Malignant Melanoma Cells

Tong

Jin

2022

Disease Markers

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Skp2 participates in the regulation of cell growth cycle and promotes the growth of tumor cells. It was speculated that miR-590-5p could regulate the expression of Skp2 and have therapeutic effects on malignant melanin. In this study, the expression of Skp2 was detected by qRT-PCR and Western blot (WB), and the targeted binding between miR-590-5p and Skp2 was verified by dual luciferase reporting assay. Subsequently, cell proliferation activity was detected by CCK8, cell invasion was detected by Transwell, and cell apoptosis was detected by mitochondrial membrane potential assay. The results indicate that Skp2 is highly expressed in melanoma cells and inhibits the proliferation and invasion of melanoma cells. However, miR-590-5p can bind to Skp2 in a targeted manner. miR-590-5p is underexpressed in melanoma cells, and its overexpression can inhibit Skp2 expression and proliferation and invasion of melanoma cells. Our results showed that miR-590-5p could inhibit melanoma cell development by targeting Skp2. This study provides more therapeutic targets for the treatment of melanoma.

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Discriminative SKP2 Interactions with CDK-Cyclin Complexes Support a Cyclin A-Specific Role in p27KIP1 Degradation

Abstract: Graphical abstract

Cited by 13 publications

References 60 publications

Ethanol Extract of Citrus grandis ‘Tomentosa’ Exerts Anticancer Effects by Targeting Skp2/p27 Pathway in Non‐Small Cell Lung Cancer

Ethanol Extract of Citrus grandis ‘Tomentosa’ Exerts Anticancer Effects by Targeting Skp2/p27 Pathway in Non‐Small Cell Lung Cancer

Emerging approaches to CDK inhibitor development, a structural perspective

miR-590-5p Targets Skp2 to Inhibit the Growth and Invasion of Malignant Melanoma Cells

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