Off-target response of a Wip1 chemical inhibitor in skin keratinocytes

Lee, Ji‐Seon; Park, Jeong-Rak; Kwon, Ok‐Seon; Kim, Hyongbum; Fornace, Albert J.; Cha, Hyuk‐Jin

doi:10.1016/j.jdermsci.2013.09.003

Cited by 21 publications

(14 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Wip1 protein downregulation during diverse events other than the cell‐cycle process was reported in multiple studies [Zhang et al, ; Crescenzi et al, ]. We also observed that the Wip1 protein levels were markedly downregulated after ultra‐violet (UV) exposure [Lee et al, ]. Of note, we also observed that Wip1 chemical inhibitor treatment facilitated Wip1 protein downregulation [Lee et al, ], suggesting that Wip1 protein downregulation might be controlled by its own phosphatase activity.…”

Section: Resultssupporting

confidence: 60%

Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 is Necessary for Normal Mitotic Progression

et al. 2015

Self Cite

View full text Add to dashboard Cite

Wip1 belongs to the protein phosphatase C (PP2C) family, of which expression is up-regulated by a number of external stresses, and serves as a stress modulator in normal physiological conditions. When overexpressed, premature dephosphorylation of stress-mediators by Wip1 results in abrogation of tumor surveillance, thus Wip1 acts as an oncogene. Previously, the functional regulation of Wip1 in cell-cycle progression by counteracting cellular G1 and G2/M checkpoint activity in response to DNA damage was reported. However, other than in stress conditions, the function and regulatory mechanism of Wip1 has not been fully determined. Herein, we demonstrated that protein regulation of Wip1 occurs in a cell cycle-dependent manner, which is directly governed by APC/C(Cdh1) at the end of mitosis. In particular, we also showed evidence that Wip1 phosphatase activity is closely associated with its own protein stability, suggesting that reduced phosphatase activity of Wip1 during mitosis could trigger its degradation. Furthermore, to verify the physiological role of its phosphatase activity during mitosis, we established doxycycline-inducible cell models, including a Wip1 wild type (WT) and phosphatase dead mutant (Wip1 DA). When ectopically expressing Wip1 WT, we observed a delay in the transition from metaphase to anaphase. In conclusion, these studies show that mitotic degradation of Wip1 by APC/C(Cdh1) is important for normal mitotic progression.

show abstract

Section: Resultssupporting

confidence: 60%

Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 is Necessary for Normal Mitotic Progression

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…Lee et al (12) revealed a significant increase in UV-induced apoptosis by Wip1 knockout in mice or human keratinocytes. A Wip1 inhibitor, CCT007093, has also been reported to increase apoptosis in breast cancer cells and skin keratinocytes (12). A previous study by Yang et al (13) assessed tumor specimens derived from breast cancer patients for Wip1 mRNA and protein expression using semi-quantitative RT-PCR, immunohistochemistry and western blotting, and demonstrated that expression of Wip1 was significantly higher in breast cancer tissues than in adjacent, normal breast tissues.…”

Section: Discussionmentioning

confidence: 99%

Wip1 regulates SKOV3 cell apoptosis through the p38 MAPK signaling pathway

Feng¹,

Liu²,

Du³

et al. 2017

Molecular Medicine Reports

View full text Add to dashboard Cite

The aim of the present study was to explore the effect of silencing wild-type p53-induced phosphatase 1 (Wip1) on apoptosis of human ovarian cancer SKOV3 cells. SKOV3 cells cultured in vitro were divided into three groups: untreated cells, cells transfected with control small interfering RNA (siRNA) and cells transfected with siRNA targeting Wip1. Flow cytometry analysis was used to detect cell apoptosis. Western blot analysis was performed to determine expression of tumor protein 53 (p53), cleaved caspase-3, caspase-3, BCL2 associated X (Bax), BCL2 apoptosis regulator (Bcl-2), p38 mitogen-activated protein kinase (p38 MAPK) and phosphorylated (p)-p38 MAPK. Reverse transcription-quantitative polymerase chain reaction was used to detect expression of p53, Bax, Bcl-2 and caspase-3 mRNAs. Compared with control, apoptosis of SKOV3 cell was significantly increased following Wip1 siRNA silencing. Wip1 silencing also resulted in a significant increase of p53 and p-p38 MAPK expression, as well as increased cleaved caspase-3/caspase-3 and Bax/Bcl-2 protein ratios. No significant differences were observed in apoptosis and apoptosis-related protein expression in the control siRNA transfected cells. The present study demonstrated that Wip1 silencing promotes apoptosis of human ovarian cancer SKOV3 cells by activation of the p38 MAPK signaling pathways and through subsequent upregulation of p53, and cleaved caspase-3/caspase-3 and Bax/Bcl-2 protein ratios. Overall, the findings of the present study suggest that targeting Wip1 may be a potential therapeutic avenue for the treatment of human ovarian cancer in the future.

show abstract

“…Some of them are substrate-based cyclic phosphopeptides that act as competitors to Wip1, but these peptides suffer from poor absorption or permeation into cells because of their large molecular weight38. CCT007093, the first generation chemical inhibitor of Wip1, has off-targets effects39. 2,4-bisarylthiazoles induce apoptosis of PPM1D amplified cell-lines, but without significant inhibition of Wip1 phosphatase activity40.…”

Section: Discussionmentioning

confidence: 99%

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Chen

Wang

Yao

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53’s tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.

show abstract

Off-target response of a Wip1 chemical inhibitor in skin keratinocytes

Cited by 21 publications

References 42 publications

Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 is Necessary for Normal Mitotic Progression

Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 is Necessary for Normal Mitotic Progression

Wip1 regulates SKOV3 cell apoptosis through the p38 MAPK signaling pathway

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Contact Info

Product

Resources

About