Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction

Gilmartin, Aidan G.; Faitg, Thomas; Richter, Mark C.; Groy, Arthur; Seefeld, Mark A.; Darcy, Michael G.; Peng, Xin; Federowicz, Kelly; Yang, Jing; Zhang, Shuyun; Minthorn, Elisabeth A.; Jaworski, Jon-Paul; Schaber, Michael D.; Martens, Stan; McNulty, Dean E.; Sinnamon, Robert H.; Zhang, Hong; Kirkpatrick, Robert B.; Nevins, Neysa; Cui, Guanglei; Pietrak, Beth; Diaz, Elsie; Jones, Amber; Brandt, Martín; Schwartz, Benjamin; Heerding, Dirk A.; Kumar, Rakesh

doi:10.1038/nchembio.1427

Cited by 176 publications

(205 citation statements)

References 31 publications

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“…A variety of genetic mouse models have shown that increased mTORC1 activity induces HSC hyperproliferation and a loss of quiescence, which ultimately leads to HSC exhaustion 36,[46][47][48] . However, activation of mTORC1 by Wip1 deletion did not lead to HSC exhaustion in the 49 might come at a cost of accelerated aging in HSC compartments. Given that Wip1 deficiency impairs HSC function via a p53-dependent but p21-independent differentiation checkpoint, determining the direct target of p53 that regulates the differentiation decision of HSCs will be of great interest.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Morita

et al. 2015

Nat Commun

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Wild-type p53-induced phosphatase 1 (Wip1) negatively regulates several tumour suppressor and DNA damage response pathways. However, the impact of Wip1 on haematopoietic stem cell (HSC) homeostasis and aging remains unknown. Here we show that Wip1 is highly expressed in HSCs but decreases with age. Wip1-deficient (Wip1 À / À ) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity. Deletion of p53 rescued the multilineage repopulation defect of Wip1 À / À HSCs without affecting cellular senescence or apoptosis, indicating that the Wip1-p53 axis regulates HSC differentiation in a manner independent of conventional p53 pathways. However, p53 deletion did not influence the increased HSC pool size in Wip1 À / À mice. Interestingly, the expansion of HSCs in Wip1 À / À mice was due to an mTORC1-mediated HSC proliferation. Thus, our study reveals a mechanism of stem cell aging, in which distinct effects of p53 and mTORC1 pathways on HSC aging are governed by Wip1.

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Section: Discussionmentioning

confidence: 99%

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

Chen

Morita

et al. 2015

Nat Commun

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“…Consistent with this is the finding that positive regulators of checkpoint recovery in G2 are commonly overexpressed in cancer and associated with poor prognosis (Bulavin et al, 2002;Cholewa et al, 2013;Li et al, 2002;Wang et al, 2008;Wierstra, 2013). Conversely, tumorigenesis is impaired in their absence (Bulavin et al, 2004;Wang et al, 2009), and several regulators of G2 checkpoint recovery are under (pre)clinical evaluation (Gilmartin et al, 2014;Gumireddy et al, 2005;Stadler et al, 2014). Understanding the mechanisms underlying cellular fate will allow us to devise new therapeutic strategies to sensitise cancer cells to DNA-damaging agents currently used in the clinic.…”

Section: Discussionmentioning

confidence: 99%

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Shaltiël

Krenning

Bruinsma

et al. 2015

Journal of Cell Science

247

263

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Cell cycle checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-damageinduced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA damage checkpoints, before discussing when and how cell fate decisions after a DSB are made.

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“…[11][12][13] Wip1 is recognized as a novel oncogene and is widely believed to be a promising therapeutic target for cancers. 14,15 The roles of Wip1 in the hematopoietic system recently caused much attention. Wip1 critically regulates granulocyte development and function via p38 mitogen-activated protein kinase/signal transducer and activator of transcription 1-dependent pathways.…”

Section: Introductionmentioning

confidence: 99%

Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner

Chen

et al. 2015

Blood

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Key Points• Wip1 controls antigenindependent B-cell development in the bone marrow via a p53-dependent pathway.• Wip1 is essential to prevent an aging-related decline in B-cell development.Wild-type p53-induced phosphatase 1 (Wip1), a phosphatase previously considered as an oncogene, has been implicated in the regulation of thymus homeostasis and neutrophil maturation. However, the role of Wip1 in B-cell development is unknown. We show that Wip1-deficient mice exhibit a significant reduction of B-cell numbers in the bone marrow, peripheral blood, and spleen. A reciprocal transplantation approach revealed a cell-intrinsic defect in early B-cell precursors caused by Wip1 deficiency. Further experiments revealed that Wip1 deficiency led to a sustained activation of p53 in B cells, which led to increased level of apoptosis in the pre-B-cell compartment. Notably, the impairment of B-cell development in Wip1-deficient mice was completely rescued by genetic ablation of p53, but not p21. Therefore, loss of Wip1 phosphatase induces a p53-dependent, but p21-independent, mechanism that impairs B-cell development by enhancing apoptosis in early B-cell precursors. Moreover, Wip1 deficiency exacerbated a decline in B-cell development caused by aging as evidenced in mice with aging and mouse models with serial competitive bone marrow transplantation, respectively. Our present data indicate that Wip1 plays a critical role in maintaining antigen-independent B-cell development in the bone marrow and preventing an aging-related decline in B-cell development. (Blood. 2015;126(5):620-628)

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Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction

Cited by 176 publications

References 31 publications

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

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

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner

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