Wip1 phosphatase: between p53 and MAPK kinases pathways

Goloudina, Anastasia R.; Кочеткова, Елена; Поспелова, Т. В.; Demidov, Oleg N.

doi:10.18632/oncotarget.7325

Cited by 62 publications

(47 citation statements)

References 81 publications

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“…As a prominent modulator of the p53 system, Wip1 provides an entry point for crosstalk between the DNA damage response and other major signaling pathways. It has been reported that its expression levels are regulated by MAP kinase signaling [49], NF-κB activity [50] and the tumor suppressor HIPK2 [51].…”

Section: Discussionmentioning

confidence: 99%

Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells

Moenke¹,

Christiano

Finzel

et al. 2016

Preprint

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Cellular signaling systems precisely transmit information in the presence of molecular noise while retaining flexibility to accommodate the needs of individual cells. To understand design principles underlying such versatile signaling, we analyzed the response of the tumor suppressor p53 to varying levels of DNA damage in hundreds of individual cells and observed a switch between distinct signaling modes characterized by isolated pulses and sustained oscillations of p53 accumulation. Guided by dynamic systems theory we show that this requires an excitable network structure comprising positive feedback and provide experimental evidence for its molecular identity. The resulting data-driven model reproduced all features of measured signaling responses and is sufficient to explain their heterogeneity in individual cells. We present evidence that heterogeneity in the levels of the feedback regulator Wip1 sets cell-specific thresholds for p53 activation, providing means to modulate its response through interacting signaling pathways. Our results demonstrate how excitable signaling networks can provide high specificity, sensitivity and robustness while retaining unique possibilities to adjust their function to the physiology of individual cells.To ensure reliable information processing, cellular signaling systems need to faithfully sense inputs in noisy environments while maintaining the flexibility to adjust their function to different physiologies. A commonly observed strategy to enable robust signal detection is the pulsed activation of signaling pathways in a digital-like response 1 . To understand how pulsatile dynamics can mediate robust yet versatile signal processing, it is necessary to identify the design principles that enable molecular networks to switch between different dynamic states and the mechanisms that allow modulation of their activity.A well-known example of a pulsatile signaling pathway in mammalian cells is the tumor suppressor p53. As a central hub of the cellular stress response, p53 maintains genomic integrity in proliferating cells and during tissue homeostasis 2 . In healthy cells, p53 levels are low due to poly-ubiquitination by the E3-ligase Mdm2 and subsequent proteasomal degradation 3,4 . Upon stress, p53 is activated by kinases that serve as primary damage sensors. One particularly dangerous insult is DNA damage in the form of double strand breaks (DSB), which may cause genomic rearrangements such as translocations, deletions and chromosome fusions. The primary sensor for DSBs is the PI3K-like kinase ataxia telangiectasia mutated (ATM) 5 , which gets phosphorylated and activated within minutes after damage induction 6 . Active ATM then stabilizes p53 by at least two distinct mechanisms: it phosphorylates Mdm2, which induces its auto-ubiquitination and subsequent degradation 7 , and p53, which interferes with Mdm2 binding 8,9 . As a consequence, p53 accumulates in the nucleus, where it acts as a transcription factor activating the expression of hundreds of target genes 10 .A key feature ...

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Section: Discussionmentioning

confidence: 99%

Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells

Moenke¹,

Christiano

Finzel

et al. 2016

Preprint

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“…All these results further support the role of Wip1 in regulating tumorigenesis. Interestingly, Wip1 overexpression in mice does not lead to spontaneous tumor appearance (18), and Wip1 overexpression in the mammary gland epithelium is also not sufficient to induce cancer (2, 19). 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.…”

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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“…These features are mainly connected with Wip1 ability to regulate DNA damage response (DDR) signaling and MAPK kinases pathway p53 network, including p38, p53, ATM, Chk2, and γ-H2AX [10,31,32]. Accumulating studies identified that high Wip1 expression disrupted the homeostasis maintained by the p38 MAPK-p53-Wip1 pathway, which caused downstream Wnt-p53 inactivation through p38 MAPK dephosphorylation, and promoted the development of malignant in humans by reducing p16 protein levels [33,34]. Our previous data have indicated that Wip1 is oncogenic and is involved in invasive growth in renal cancer cells and ICC cells [12,17].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-129-2-3p directly targets Wip1 to suppress the proliferation and invasion of intrahepatic cholangiocarcinoma

Chen¹,

Jiang²,

Fang³

et al. 2020

J. Cancer

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Accumulated studies showed that numerous microRNAs (miRNAs) were aberrantly expressed in human intrahepatic cholangiocarcinoma (ICC) and contributed to the tumorigenic processes. However, whether miR-129-2-3p is implicated in the ICC initiation and progression is still limited. Here, the results revealed that miR-129-2-3p expression was notably decreased in ICC tissues and cell lines, and that a low miR-129-2-3p expression was obviously associated with distant metastasis and clinical stage. Exogenous miR-129-2-3p expression evidently repressed the proliferative and invasive abilities of ICC cells. Mechanistic studies indicated that Wild-type p53-induced phosphatase 1 (Wip1) was a direct target gene for miR-129-2-3p in ICC cells. Furthermore, silencing Wip1 expression mimicked the suppressive effects of miR-129-2-3p upregulation on ICC cells. Interestingly, reintroduction of Wip1 expression partially abolished the miR-129-2-3p -reduced cell proliferation and invasion in ICC. Moreover, ectopic miR-129-2-3p expression hindered the ICC tumor growth in vivo. To the best of our knowledge, it is the first time to reveal that miR-129-2-3p plays a crucial role in tumor suppression in ICC pathogenesis through directly targeting Wip1. These results will aid in elucidating the roles of miR-129-2-3p in ICC, and suggest that this miRNA may provide a potential target for the treatment of ICC

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Wip1 phosphatase: between p53 and MAPK kinases pathways

Cited by 62 publications

References 81 publications

Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells

Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells

Phosphatase Wip1 in Immunity: An Overview and Update

MicroRNA-129-2-3p directly targets Wip1 to suppress the proliferation and invasion of intrahepatic cholangiocarcinoma

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