Skp2 is required for Aurora B activation in cell mitosis and spindle checkpoint

Wu, Juan; Huang, Yu Fan; Zhou, Xin; Zhang, Wei; Lian, Yi; Lv, Xiao; Gao, Xiu; Lin, Hui Kuan; Zeng, Yi Xin; Huang, Jian

doi:10.1080/15384101.2015.1120916

Cited by 14 publications

(15 citation statements)

References 27 publications

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“…Recent studies reported that overexpressed Skp2 was found in paclitaxel-resistant prostate cancer cells ( Yang et al, 2016 ; Byun et al, 2018 ; Gong et al, 2018 ), and knockdown of Skp2 restored the sensitivity of paclitaxel in prostate cancer cells ( Byun et al, 2018 ). Skp2 also plays a pivotal role in mitosis and spindle checkpoint by triggering ubiquitination and activation of Aurora-B ( Nakayama et al, 2004 ; Sugihara et al, 2006 ; Hu and Aplin, 2008 ; Wu et al, 2015 ). Skp2 depletion in melanoma cells resulted in a G2-M phase arrest ( Hu and Aplin 2008 ), and suppression of both BRAF (V600E) and Skp2 inhibited cell growth and invasion in melanoma cell lines( Sumimoto et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

et al. 2021

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Melanoma is one of the deadliest skin cancers having a five-year survival rate around 15–20%. An overactivated MAPK/AKT pathway is well-established in BRAF mutant melanoma. Vemurafenib (Vem) was the first FDA-approved BRAF inhibitor and gained great clinical success in treating late-stage melanoma. However, most patients develop acquired resistance to Vem within 6–9 months. Therefore, developing a new treatment strategy to overcome Vem-resistance is highly significant. Our previous study reported that the combination of a tubulin inhibitor ABI-274 with Vem showed a significant synergistic effect to sensitize Vem-resistant melanoma both in vitro and in vivo. In the present study, we unveiled that VERU-111, an orally bioavailable inhibitor of α and β tubulin that is under clinical development, is highly potent against Vem-resistant melanoma cells. The combination of Vem and VERU-111 resulted in a dramatically enhanced inhibitory effect on cancer cells in vitro and Vem-resistant melanoma tumor growth in vivo compared with single-agent treatment. Further molecular signaling analyses demonstrated that in addition to ERK/AKT pathway, Skp2 E3 ligase also plays a critical role in Vem-resistant mechanisms. Knockout of Skp2 diminished oncogene AKT expression and contributed to the synergistic inhibitory effect of Vem and VERU-111. Our results indicate a treatment combination of VERU-111 and Vem holds a great promise to overcome Vem-resistance for melanoma patients harboring BRAF (V600E) mutation.

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Section: Discussionmentioning

confidence: 99%

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

et al. 2021

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“…The in vivo ubiquitination assay was performed as described elsewhere 51. In brief, 293T cells were transiently transfected with indicated plasmids for 36 h. Transfected cells were harvested by denatured buffer (6 M guanidine-HCl, 0.1 M Na 2 HPO 4 /NaH 2 PO 4 , 10 mM imidazole).…”

Section: Methodsmentioning

confidence: 99%

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

Lian¹,

Huang²,

Zhang³

et al. 2019

Theranostics

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Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.Methods: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation. Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP. The regulatory mechanism of RNF41-CACYBP signaling axis on P27Kip1 was investigated by western blotting and immunofluorescence.Results: CACYBP was highly expressed and associated with poor prognosis in HCC. CACYBP expression was required for HCC cell growth in vitro and in vivo. Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels. RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome- and lysosome-dependent pathways. In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression. Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27Kip1 and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon. CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells. P27Kip1-S10D but not P27Kip1-S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.Conclusion: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.

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“…In addition to the proteolytic function of SKP2, recent studies have revealed that SKP2 exerts its oncogenic activity by mediating the conjugation of lysine-63 (K63)-linked polyubiquitin chains to target proteins such as protein kinase B (PKB; also known as AKT) [42], Yes-associated protein (YAP) [43], Twist transcriptional factor [44], Nijmegen breakage syndrome 1 (NBS1) [45], Ras related GTP binding A (RAG-A) [46], Breakpoint cluster region-Abelson (BCR-ABL) [47], human MutT homolog 1 (MTH1) [48], and Aurora-B [49], which results in the stabilization or alters the localization of these proteins or promotes the recruitment of interactors. The K63-linked ubiquitylation of the protein kinase AKT by SCF SKP2 is stimulated by growth factors and cytokines, and it facilitates the recruitment of AKT to the plasma membrane, with its resulting hyperactivation leading to up-regulation of glycolysis and promotion of tumorigenesis [42,50].…”

Section: Fbxl1 (Skp2)mentioning

confidence: 99%

F-Box Proteins and Cancer

Yumimoto

Yamauchi

Nakayama

2020

Cancers

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Controlled protein degradation is essential for the operation of a variety of cellular processes including cell division, growth, and differentiation. Identification of the relations between ubiquitin ligases and their substrates is key to understanding the molecular basis of cancer development and to the discovery of novel targets for cancer therapeutics. F-box proteins function as the substrate recognition subunits of S-phase kinase-associated protein 1 (SKP1)−Cullin1 (CUL1)−F-box protein (SCF) ubiquitin ligase complexes. Here, we summarize the roles of specific F-box proteins that have been shown to function as tumor promoters or suppressors. We also highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box proteins, and discuss how these F-box proteins are deployed to regulate their cognate substrates in various situations.

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Skp2 is required for Aurora B activation in cell mitosis and spindle checkpoint

Abstract: y These authors contributed equally to this work.

Cited by 14 publications

References 27 publications

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

F-Box Proteins and Cancer

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Skp2 is required for Aurora B activation in cell mitosis and spindle checkpoint

Abstract: y These authors contributed equally to this work.

Cited by 14 publications

References 27 publications

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

F-Box Proteins and Cancer

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CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation