Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23

Li, Jing; Yang, Ying; Yue, Peng; Austin, Robert J.; Eyndhoven, W.G van; Nguyen, Ken; Gabriele, Tim; McCurrach, Mila E.; Marks, Jeffrey R.; Hoey, Timothy; Lowe, Scott W.; Powers, Scott

doi:10.1038/ng888

Cited by 239 publications

(223 citation statements)

References 13 publications

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“…Thus, although we expected to see a substantial tumorprone phenotype in MMTV-PPM1D transgenic mice, they actually remained tumor-free. This further supports the notion that Wip1 behaves as a modulator of tumorigenesis and a weak oncogene in vivo (Bulavin et al, 2002;Li et al, 2002). Wip1 overexpression using an MMTV promoter does not have any overt effect on mammary gland development.…”

supporting

confidence: 85%

“…Further evidence with a rodent fibroblast transformation assay showed that introduction of Wip1 along with Ras, Myc, or ErbB2 resulted in enhanced colony formation in soft agar and led to the development of tumors when these cells were explanted into nude mice (Bulavin et al, 2002). These findings suggested that Wip1 phosphatase has oncogenic potential (Bulavin et al, 2002;Li et al, 2002;Hirasawa et al, 2003;Saito-Ohara et al, 2003).…”

mentioning

confidence: 99%

“…Through a combination of genetic and molecular studies, it was established that Wip1 functions in a linear pathway with p53 (Bulavin et al, 2002;Li et al, 2002). A large majority of primary breast tumors that overexpress Wip1 have a structurally intact p53 gene, implying that Wip1 may contribute to the functional inactivation of p53 (Bulavin et al, 2002;Rauta et al, 2006).…”

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confidence: 99%

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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: 85%

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confidence: 99%

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confidence: 99%

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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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“…Wip1 is induced by DNA damage in a p53-dependent manner, and inhibits ultraviolet (UV)-irradiation-induced p38 activation by dephosphorylating Thr180 in p38, thereby inhibiting the function of p53. 24,25 It has been reported that the Wip1 (PPM1D) gene is amplified or overexpressed in various human cancers, including breast cancers, [26][27][28][29] and that overexpression of Wip1 (PPM1D) complements the oncogenes Ras, Myc, and Neu1 for transformation of wild-type mouse embryonic fibroblasts (MEFs). 26 More recently, it has been shown that Wip1 associates with the nuclear isoform of uracil DNA glycosylase, UNG2, and that Wip1 suppresses DNA damage-induced base excision repair (BER) activity by dephosphorylating and inactivating UNG2.…”

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confidence: 99%

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

et al. 2005

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The antioncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell-cycle checkpoint regulation. Here we show that Chk2 associates with the oncogenic protein Wip1 (wild-type p53-inducible phosphatase 1) (PPM1D), a p53-inducible protein phosphatase. Phosphorylation of Chk2 at threonine68 (Thr68), a critical event for Chk2 activation, which is normally induced by DNA damage or overexpression of Chk2, is inhibited by expression of wild-type (WT), but not a phosphatase-deficient mutant (D314A) of Wip1 in cultured cells. Furthermore, an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. Moreover, inhibition of Wip1 expression by RNA interference results in abnormally sustained Thr68 phosphorylation of Chk2 and increased susceptibility of cells in response to DNA damage, indicating that Wip1 acts as a negative regulator of Chk2 in response to DNA damage.

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“…PS6K is a ribosomal protein that is involved in the progression from the G1 to S phase of the cell cycle. It is rapidly activated in response to mitogenic stimuli, for example, growth factors, cytokines, and oncogene products (Grove et al, 1991;Lane et al, 1993;Chou et al, 1995;Grammer et al, 1996;Thomas et al, 1997;Couch et al, 1999;Barlund et al, 2000b;Wu et al, 2000;Latham et al, 2001;Monni et al, 2001;Andersen et al, 2002;Li et al, 2002;Sinclair et al, 2002;Sinclair et al, 2003).…”

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confidence: 99%

Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients

et al. 2004

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The RPS6KB1 gene is amplified and overexpressed in approximately 10% of breast carcinomas and has been found associated with poor prognosis. We studied the prognostic significance of P70 S6 kinase protein (PS6K) overexpression in a series of 452 nodenegative premenopausal early-stage breast cancer patients (median follow-up: 10.8 years). Immunohistochemistry was used to assess PS6K expression in the primary tumour, which had previously been analysed for a panel of established prognostic factors in breast cancer. In a univariate analysis, PS6K overexpression was associated with worse distant disease-free survival as well as impaired locoregional control (HR 1.80, P 0.025 and HR 2.50, P 0.006, respectively). In a multivariate analysis including other prognostic factors, PS6K overexpression remained an independent predictor for poor locoregional control (RR 2.67, P 0.003). To our knowledge, P70 S6 kinase protein is the first oncogenic marker that has prognostic impact on locoregional control and therefore may have clinical implications in determining the local treatment strategy in early-stage breast cancer patients. The treatment of breast cancer is guided by risk factors. Approximately 70% of all node-negative breast cancer patients can be cured by locoregional therapy alone. This automatically implies that the remaining 30% of these patients will develop a recurrence despite adequate locoregional therapy. Currently, treatment strategy in breast cancer is based upon tumour stage, grade, and hormone receptor status. Additional prognostic factors are greatly needed, first to select those patients who might benefit from adjuvant systemic therapy and second to optimise locoregional therapy in order to avoid locoregional recurrences.The prognostic significance of a considerable number of tumour markers has already been investigated but to date, none of these factors can be used to guide the treatment of primary breast cancer.A recent study by Barlund et al (2000a) demonstrated that amplification of a putative tumour marker called P70 S6 kinase protein (PS6K) might be associated with poor outcome in breast cancer. In addition, the authors reported that RPS6KB1 gene amplification and PS6K overexpression are significantly correlated.The RPS6KB1 gene is located at 17q23 and amplified in approximately 10% of all primary breast cancer cases. PS6K is a ribosomal protein that is involved in the progression from the G1 to S phase of the cell cycle. It is rapidly activated in response to mitogenic stimuli, for example, growth factors, cytokines, and oncogene products (Grove et

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Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23

Cited by 239 publications

References 13 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

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients

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