Smurf1 controls S phase progression and tumorigenesis through Wee1 degradation

Wei, Ru‐Dong; Guo, Jing; Li, Mengyuan; Yang, Xiubin; Zhu, Ruimin; Huang, Hao; Li, Kejuan; Zhang, Lingqiang; Gao, Ran

doi:10.1002/1873-3468.12624

Cited by 9 publications

(5 citation statements)

References 26 publications

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“…Smurf1, as a E3 Ubiquitin Ligases, could degrade the key protein in the TGF-β1 induced pathway. 27,28 PTEN, an upstream molecule of PI3K-Akt-mTOR pathway, could dephosphorylate the PI3K to down-regulate the activation of PI3K-Akt-mTOR pathway. 29,30 WWP2, another E3 Ubiquitin Ligases, could degrade PTEN by ubiquitination pathway to suppress tumourigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The potential mechanisms of Bortezomib inhibiting the expression of Smurf1 maybe that Bortezomib promotes the expression of inhibitory miRNA, such as miR-424(322). Smurf1, as a E3 Ubiquitin Ligases, could degrade the key protein in the TGF-β1 induced pathway 27,28. PTEN, an upstream molecule of PI3K-Akt-mTOR pathway, could dephosphorylate the PI3K to down-regulate the activation of PI3K-Akt-mTOR pathway 29,30.…”

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confidence: 99%

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Bortezomib attenuates renal interstitial fibrosis in kidney transplantation via regulating the EMT induced by TNF‐α‐Smurf1‐Akt‐mTOR‐P70S6K pathway

Zhou

Cheng

Wang

et al. 2019

J Cellular Molecular Medi

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Allograft interstitial fibrosis was characterized by massive extracellular matrix deposition caused by activated fibroblasts and myofibroblasts. Epithelial‐mesenchymal transition (EMT) is recognized as an important source of myofibroblasts contributing to the pathogenesis of allograft interstitial fibrosis. Smad ubiquitination regulatory factor 1 (Smurf1) has been recently reported to be involved in the progression of EMT. Our study was to detect the effect of Bortezomib and Smurf1 in the EMT and allograft interstitial fibrosis. Biomarkers of EMT, as well as Smurf1, were examined in human proximal tubular epithelial cells (HK‐2) treated with tumour necrosis factor‐alpha (TNF‐α) in various doses or at various time points by Western Blotting or qRT‐PCR. We knockdown or overexpressed Smurf1 in HK‐2 cells. Furthermore, rat renal transplant model was established and intervened by Bortezomib. Allograft tissues from human and rats were also collected and prepared for HE, Masson's trichrome, immunohistochemical staining and western blotting assays. As a result, we found that TNF‐α significantly promoted the development of EMT in a time‐dependent and dose‐dependent manner through Smurf1/Akt/mTOR/P70S6K signalling pathway. More importantly, Bortezomib alleviated the progression of EMT and allograft interstitial fibrosis in vivo and in vitro by inhibiting the production of TNF‐α and expression of Smurf1. In conclusion, Smurf1 plays a critical role in the development of EMT induced by TNF‐α. Bortezomib can attenuate the Sumrf1‐mediated progression of EMT and renal allograft interstitial fibrosis, which could be suggested as a novel choice for the prevention and treatment of renal allograft interstitial fibrosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Bortezomib attenuates renal interstitial fibrosis in kidney transplantation via regulating the EMT induced by TNF‐α‐Smurf1‐Akt‐mTOR‐P70S6K pathway

Zhou

Cheng

Wang

et al. 2019

J Cellular Molecular Medi

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“…Christopher C. Porter et al reported that the inhibition of WEE1 prevents cytarabine-induced S phase arrest in acute myeloid leukemia 14. Moreover, Wei et al demonstrated that WEE1 degradation contributes to Smurf1-regulated S phase progression 15. Therefore, WEE1 upregulation may explain the S phase arrest after SMYD3 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of SMYD3 in Ovarian Cancer is Associated with Ovarian Cancer Proliferation and Apoptosis via Methylating H3K4 and H4K20

et al. 2019

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Background : Epigenetic regulation has been verified as a key mechanism in tumorigenesis. SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase, is a promising epigenetic therapeutic target and is overexpressed in numerous human tumors. SMYD3 can promote oncogenic progression by methylating lysines to integrate cytoplasmic kinase signaling cascades or by methylating histone lysines to regulate specific gene transcription. However, the exact role of SMYD3 in the progression of ovarian cancer is still unknown. Methods : Immunohistochemistry was employed to test SMYD3 expression in ovarian cancer tissues from clinical patients. CCK-8 assay, Real-time cell analysis (RTCA), colony formation assay, cell cycle and apoptosis tested by Flow cytometer were employed to test the effects of SMYD3 on cell proliferation and apoptosis in ovarian cancer cell lines. A PCR array was used to identify the downstream targets of SMYD3. And, PCR and Western blot were used to verify their expression. The binding of SMYD3 on the promoter of target genes were tested by ChIP assays. We also use nude mice subcutaneous tumor model and patient-derived xenograft (PDX) model to investigate the tumor promotive function of SMYD3 in vivo . Results : SMYD3 expression was higher in ovarian cancer tissues and cell lines than in normal ovarian epithelial tissue and human ovarian surface epithelial cells (HOSEpiC). After silencing SMYD3, the proliferation of ovarian cancer cells was significantly inhibited in vitro . In addition, the SMYD3-specific small-molecule inhibitor BCI-121 suppressed ovarian cancer cell proliferation. Downregulation of SMYD3 led to S phase arrest and increased the cell apoptosis rate. Furthermore, a PCR array revealed that SMYD3 knockdown caused the upregulation of the cyclin-dependent kinase (CDK) inhibitors CDKN2A (p16 INK4 ), CDKN2B (p15 INK4B ), CDKN3 and CDC25A, which may be responsible for the S phase arrest. In addition, the upregulation of CD40LG and downregulation of BIRC3 may explain the increased cell apoptosis rate after silencing SMYD3. We also discovered that SMYD3 bound on the promoter of CDKN2A and down-regulated its expression by triple-methylating H4K20. In addition, SMYD3 bound on the promoter of BIRC3 and up-regulated its expression by triple-methylating H3K4. Finally, knocking down SMYD3 could inhibit ovarian cancer growth in nude mice subcutaneous tumor model and PDX model. Conclusion : Our results demonstrated that SMYD3 was overexpressed in ovarian cancer and contributes to the regulation of tumor proliferation and apoptosis via SMYD3-H4K20me3-CDKN2A pathway and SMYD3-H3K4me3-BIRC3 pathway. Thus, SMYD3 is a promising epigenetic therapeutic target for ovarian cancer.

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“…During M-phase, ubiquitin-dependent protein degradation is responsible for the downfall of WEE1. Initially, during the G2-M transition, PLK1, CDK1, and CK2 phosphorylation at S53, S123, and S121 residues generate phosphodegrons (PDs), and CDC34 ubiquitination of WEE1 allows SCF (skp1/cul1/F-box) β-TrCP (β-transduction repeat-containing protein), Tome-1 (trigger-of-mitotic-entry 1), Smurf1 (Smad ubiquitination regulatory factor1), and Pof1/3 (Promoter of Filamentation1/3) (in fission yeast) mediated WEE1 degradation. − However, in a later study, WEE1 was found to interact with the β-subunit of CK2, but this interaction showed no remarkable influence on WEE1 kinase activity . Another mechanism reported is the nuclear export of WEE1.…”

Section: Introductionmentioning

confidence: 99%

Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders

et al. 2023

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WEE1 is a checkpoint kinase critical for mitotic events, especially in cell maturation and DNA repair. Most cancer cells' progression and survival are linked with elevated levels of WEE1 kinase. Thus, WEE1 kinase has become a new promising druggable target. A few classes of WEE1 inhibitors are designed by rationale or structure-based techniques and optimization approaches to identify selective acting anticancer agents. The discovery of the WEE1 inhibitor AZD1775 further emphasized WEE1 as a promising anticancer target. Therefore, the current review provides a comprehensive data on medicinal chemistry, synthetic approaches, optimization methods, and the interaction profile of WEE1 kinase inhibitors. In addition, WEE1 PROTAC degraders and their synthetic procedures, including a list of noncoding RNAs necessary for regulation of WEE1, are also highlighted. From the standpoint of medicinal chemistry, the contents of this compilation serve as an exemplar for the further design, synthesis, and optimization of promising WEE1-targeted anticancer agents.

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Smurf1 controls S phase progression and tumorigenesis through Wee1 degradation

Cited by 9 publications

References 26 publications

Bortezomib attenuates renal interstitial fibrosis in kidney transplantation via regulating the EMT induced by TNF‐α‐Smurf1‐Akt‐mTOR‐P70S6K pathway

Bortezomib attenuates renal interstitial fibrosis in kidney transplantation via regulating the EMT induced by TNF‐α‐Smurf1‐Akt‐mTOR‐P70S6K pathway

Overexpression of SMYD3 in Ovarian Cancer is Associated with Ovarian Cancer Proliferation and Apoptosis via Methylating H3K4 and H4K20

Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders

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