Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways

Chen, Ziyang; Yi, Weiwei; Morita, Yohei; Wang, Hu; Cong, Yu‐Sheng; Liu, Junping; Xiao, Zhi‐Cheng; Rudolph, K. Lenhard; Cheng, Tao; Ju, Zhenyu

doi:10.1038/ncomms7808

Cited by 55 publications

(63 citation statements)

References 52 publications

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“…It exists in two multiprotein complexes: mTOR complex 1(mTORC1) and mTOR complex 2 (mTORC2) 13. The downstream mediators of mTORC1 include p70S6K and S6 14. In our study, naringin treatment showed significant decrease in levels of phosphor‐mTOR (Ser2481, Ser2448), phosphor‐p70S6K (Thr389) and phosphor‐S6 (Ser235/236) in HSCs which suggested mTOR pathways were inhibited by naringin.…”

Section: Resultssupporting

confidence: 52%

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Shi

Ren

Chen

et al. 2016

J Cellular Molecular Medi

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A previous study has demonstrated that Ganshuang granule (GSG) plays an anti‐fibrotic role partially by deactivation of hepatic stellate cells (HSCs). In HSCs activation, mammalian target of rapamycin (mTOR)‐autophagy plays an important role. We attempted to investigate the role of mTOR‐autophagy in anti‐fibrotic effect of GSG. The cirrhotic mouse model was prepared to demonstrate the anti‐fibrosis effect of GSG. High performance liquid chromatography (HPLC) analyses were used to identify the active component of GSG. The primary mouse HSCs were isolated and naringin was added into activated HSCs to observe its anti‐fibrotic effect. 3‐methyladenine (3‐MA) and Insulin‐like growth factor‐1 (IGF‐1) was added, respectively, into fully activated HSCs to explore the role of autophagy and mTOR. GSG played an anti‐fibrotic role through deactivation of HSCs in cirrhotic mouse model. The concentration of naringin was highest in GSG by HPLC analyses and naringin markedly suppressed HSCs activation in vitro, which suggested that naringin was the main active component of GSG. The deactivation of HSCs caused by naringin was not because of the autophagic activation but mTOR inhibition, which was supported by the following evidence: first, naringin induced autophagic activation, but when autophagy was blocked by 3‐MA, deactivation of HSCs was not attenuated or reversed. Second, naringin inhibited mTOR pathway, meanwhile when mTOR was activated by IGF‐1, deactivation of HSCs was reversed. In conclusion, we have demonstrated naringin in GSG suppressed activation of HSCs for anti‐fibrosis effect by inhibition of mTOR, indicating a potential therapeutic application for liver cirrhosis.

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Section: Resultssupporting

confidence: 52%

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Shi

Ren

Chen

et al. 2016

J Cellular Molecular Medi

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“…Therefore, Wip1 may actually not act as a cancer-initiating oncogene on its own but provides advantages for tumor development through its function on multiple target molecules. Despite substantial evidence over the last decade that defines Wip1 as an onco-protein, recent studies have also shed lights on the role of Wip1 in regulating other normal and/or pathophysiological process due to its wide range of substrates, such as autophagy (20), aging (21), adult neurogenesis (4), and liver regeneration (22). …”

Section: An Overview Of Phosphatase Wip1mentioning

confidence: 99%

Phosphatase Wip1 in Immunity: An Overview and Update

et al. 2017

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Wild-type p53-induced phosphatase 1 (Wip1) is a newly identified serine/threonine phosphatase, which belongs to the PP2C family. Due to its involvement in stress-induced networks and overexpression in human tumors, primary studies have mainly focused on the role of Wip1 in tumorigenesis. It now has also been implicated in regulating several other physiological processes such as organism aging and neurogenesis. Recent evidence highlights a new role of Wip1 in controlling immune response through regulating immune cell development and function, as well as through the interplay with inflammatory signaling pathways such NF-κB and p38 mitogen-activated protein kinase. In this short review, we will give an overview of Wip1 in immunity to better understand this important phosphatase.

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“…In particular, PPM1D knock-out mice show a p53-dependent block in T cell and B cell maturation in the thymus and bone marrow, respectively [122, 123]. In addition, WIP1 is highly expressed in various kinds of stem cells, and PPM1D knock-out mice show increased apoptosis in stem cell compartments [33, 75, 124]. Interestingly, apoptosis in WIP1-deficient intestinal and mesenchymal stem cells was rescued by loss of p53, whereas apoptosis of hematopoietic stem cells (HSC) was p53 independent [33, 75, 124].…”

Section: Role Of Wip1 In Immune Response and Hematopoiesismentioning

confidence: 99%

“…In addition, WIP1 is highly expressed in various kinds of stem cells, and PPM1D knock-out mice show increased apoptosis in stem cell compartments [33, 75, 124]. Interestingly, apoptosis in WIP1-deficient intestinal and mesenchymal stem cells was rescued by loss of p53, whereas apoptosis of hematopoietic stem cells (HSC) was p53 independent [33, 75, 124]. Loss of WIP1 led to hyper-proliferation of HSC due to the activation of mTORC1 pathway and led to premature exhaustion of HSC [124].…”

Section: Role Of Wip1 In Immune Response and Hematopoiesismentioning

confidence: 99%

“…Interestingly, apoptosis in WIP1-deficient intestinal and mesenchymal stem cells was rescued by loss of p53, whereas apoptosis of hematopoietic stem cells (HSC) was p53 independent [33, 75, 124]. Loss of WIP1 led to hyper-proliferation of HSC due to the activation of mTORC1 pathway and led to premature exhaustion of HSC [124]. On the other hand, deletion of p53 rescued the differentiation of WIP1-deficient HSCs into erythroid and myeloid lineages and the repopulation defect in lethally irradiated mice [124].…”

Section: Role Of Wip1 In Immune Response and Hematopoiesismentioning

confidence: 99%

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WIP1 phosphatase as pharmacological target in cancer therapy

2017

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DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.

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Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways

Cited by 55 publications

References 52 publications

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Phosphatase Wip1 in Immunity: An Overview and Update

WIP1 phosphatase as pharmacological target in cancer therapy

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