Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway

Bulavin, Dmitry V.; Phillips, Crissy; Nannenga, Bonnie; Timofeev, Oleg; Donehower, Larry A.; Anderson, Carl W.; Appella, Ettore; Fornace, Albert J.

doi:10.1038/ng1317

Cited by 384 publications

(425 citation statements)

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“…We found that while there was a trend in delaying the tumor onset in MMTV-ErbB2/MKK6 females, it was not significantly different from MMTV-ErbB2 mice (Figure 2c). These results were different from the effect of Wip1 ablation on a delay in tumor formation in MMTV-ErbB2 mice (Bulavin et al, 2004). To understand the potential reason for such a discrepancy, we analyzed the effect of MKK6 overexpression on the level of endogenous Wip1 in MMTV-MKK6 transgenics.…”

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confidence: 80%

“…While there was no significant difference in the rate of apoptosis between analyzed samples Several potential downstream targets of Wip1 have been identified in vitro: p38 MAPK, p53, Chk1, Chk2 and ataxia-telangiectasia mutated (ATM) (Takekawa et al, 2000;Lu et al, 2005;Fujimoto et al, 2006;Shreeram et al, 2006). The role of p38 MAPK is particularly interesting, as we previously found that Wip1-deficient mice show a p38 MAPK-dependent delay in the onset of breast cancer when crossed with MMTV-ErbB2 transgenic mice (Bulavin et al, 2004). To systematically address the significance of the p38 MAPK signaling pathway in regulation of tumorigenesis by Wip1 phosphatase, we next generated transgenic mice expressing a constitutively active form of MKK6 kinase, an upstream regulator of p38 MAPK (Raingeaud et al, 1996).…”

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confidence: 94%

“…Previous analysis showed that Wip1 could modulate apoptotic response and proliferation (Bulavin et al, 2004;Belova et al, 2005), which could explain the early onset of tumors observed in MMTV-ErbB2/ PPM1D mice. While there was no significant difference in the rate of apoptosis between analyzed samples Several potential downstream targets of Wip1 have been identified in vitro: p38 MAPK, p53, Chk1, Chk2 and ataxia-telangiectasia mutated (ATM) (Takekawa et al, 2000;Lu et al, 2005;Fujimoto et al, 2006;Shreeram et al, 2006).…”

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confidence: 98%

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The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

et al. 2006

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There is increasing evidence for the role of wild-type p53 induced phosphatase 1 (Wip1) phosphatase in the regulation of tumorigenesis. To evaluate Wip1 as a breast cancer oncogene, we generated a mouse strain with targeted expression of Wip1 to the breast epithelium. We found that these mice are prone to cancer when intercrossed with transgenics expressing the ErbB2 oncogene but not conditional knockouts for Brca2. This tumor-prone phenotype of Wip1 is fully eliminated through attenuation of proliferation by activating the MKK6/p38 mitogenactivated protein kinases (MAPK) cascade in mice bearing a constitutively active form of MKK6. We propose that Wip1 phosphatase operates within the MKK6/p38 MAPK signaling pathway to promote ErbB2-driven mammary gland tumorigenesis.

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confidence: 80%

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confidence: 94%

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confidence: 98%

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The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

et al. 2006

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“…Deficiency of the p38α upstream kinase MKK3 or MKK6 in fibroblasts has been found to be associated with increased tumorigenesis (Brancho et al, 2003). Breast tumors triggered by the MMTV-neu oncogene develop at a reduced frequency in mice deficient in Wip1, a p38α phosphatase (Bulavin et al, 2004). Moreover, a recent study showed a role for PRAK in suppressing skin carcinogenesis by mediating Rasdependent oncogenic senescence upon activation by p38α .…”

Section: P38 In Inflammation and Cancermentioning

confidence: 99%

MAPK signaling in inflammation-associated cancer development

2010

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Mitogen-activated protein (MAP) kinases comprise a family of protein-serine/threonine kinases, which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms, including mammals. These kinases, including ERKs, JNKs and p38s, are regulated by a phosphorelay cascade, with a prototype of three protein kinases that sequentially phosphorylate one another. MAPKs transduce extracellular signals into a variety of cellular processes, such as cell proliferation, survival, death, and differentiation. Consistent with their essential cellular functions, MAPKs have been shown to play critical roles in embryonic development, adult tissue homeostasis and various pathologies. In this review, we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and, particularly, inflammation-associated cancer development.

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“…The mammalian PPM1D gene coding for the nuclear PP2C delta isoform (or Wip1) was originally identified by its p53-dependent transcriptional induction in response to ionizing IR (Fiscella et al, 1997) and was thus of particular interest for further study. Mice deficient for Wip1 exhibit defects in reproductive organ and immune function, and Wip1 À/À MEF cells have decreased proliferation rates owing to the activation of the p16 (Ink4a) and p19 (ARF) pathways (Choi et al, 2002;Bulavin et al, 2004). In response to genotoxic stress, Wip1 was recently shown to downregulate several checkpoint pathways.…”

Section: Introductionmentioning

confidence: 99%

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

et al. 2006

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We previously demonstrated that type 2C protein phosphatases (PP2C) Ptc2 and Ptc3 are required for DNA checkpoint inactivation after DNA double-strand break repair or adaptation in Saccharomyces cerevisiae. Here, we show the conservation of this pathway in mammalian cells. In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop. The oncogenic protein Wip1, a PP2C phosphatase, binds Chk2 and dephosphorylates phosphoThr68. Consequently, Wip1 opposes Chk2 activation by ATM after ionizing irradiation of cells. In HCT15 colorectal cancer cells corrected for functional Chk2 activity, Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint. These results indicate that Wip1 is one of the phosphatases regulating the activity of Chk2 in response to DNA damage.

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Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway

Cited by 384 publications

References 35 publications

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

MAPK signaling in inflammation-associated cancer development

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

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