High Expression of PPM1D Induces Tumors Phenotypically Similar to TP53 Loss-of-Function Mutations in Mice.

Jelena Milosevic,Gabriel Gallo-Oller,Thale K Olsen,Per Kogner,Margareta Wilhelm,Ninib Baryawno,Tommy Martinsson,Diana Treis,Lotta H M Elfman,Susanne Fransson,Miklos Gulyas,John Inge Johnsen

doi:10.3390/cancers13215493

Jelena Milosevic, Gabriel Gallo-Oller + Show 10 more

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https://doi.org/10.3390/cancers13215493

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Abstract

Simple SummaryAberrant expression of the PPM1D gene which encodes a phosphatase called WIP1 is frequently observed in cancers of different origins. WIP1 is a negative regulator of the tumor suppressor p53. Improper inactivation of p53 results in genomic instability and can induce neoplastic transformation. We show that overexpression of PPM1D induces tumors in mice similar to cancers harboring p53 mutations. Our results suggest that PPM1D can act as an oncogenic driver by inducing genomic instability, impaired growth arrest, and apoptotic escape that can result in neoplastic transformation and malignant tumor development. PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice developed a wide variety of cancers. PPM1D-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblastic lymphoma was the most frequent cancer observed in these mice (55%) followed by adenocarcinomas (24%), leukemia (12%) and other solid tumors including neuroblastoma. Characterization of T-cell lymphomas in mice overexpressing PPM1D demonstrates Pten-deletion and p53-accumulation similar to mice with p53 loss-of-function. Also, Notch1 mutations which are recurrently observed in T-cell acute lymphoblastic lymphoma (T-ALL) were frequently detected in PPM1D-transgenic mice. Hence, PPM1D acts as an oncogenic driver in connection with cellular stress, suggesting that the PPM1D gene status and expression levels should be investigated in TP53 wild-type tumors.

Highlights

The protein phosphatase magnesium-dependent 1 delta (PPM1D) gene encodes a nuclear serine/threonine phosphatase included in the PP2C family of phosphatases named WIP1(wild-type p53-induced phosphatase 1) [1]
WIP1 is a critical regulator of DNA damage response and cell-cycle progression by its ability to regulate the activity of the tumor-suppressor protein p53, ATM, CHK1/2, and other key molecules involved in cell-cycle progression, DNA
To characterize the role of PPM1D in tumor development, we constructed genetically engineered C57BL/6N mice overexpressing WIP1 through pronuclear injection of the human PPM1D gene controlled by the rat tyrosine hydroxylase (TH) promoter (Figure 1A)

Summary

Introduction

The protein phosphatase magnesium-dependent 1 delta (PPM1D) gene encodes a nuclear serine/threonine phosphatase included in the PP2C family of phosphatases named WIP1(wild-type p53-induced phosphatase 1) [1]. MDM2 expression is induced by p53 which results in p53–MDM2 complex formation, MDM2-mediated ubiquitination, and proteasomal degradation of p53 [21]. This p53–MDM2 autoregulatory loop is controlled by ATM and ATR as well as other kinases that, immediately following DNA damage, phosphorylate MDM2 and p53 in a manner that inhibits the p53–MDM2 interaction leading to stabilization of p53 [22,23,24]. In order to restore the normal homeostatic state of the cell after completion of DNA repair, a set of phosphatases dephosphorylate p53 and MDM2 to allow for p53–MDM2 interaction and proteasomal degradation of p53. WIP1 has been shown to dephosphorylate and inactivate p53 (Ser15) as well as the p53-activating kinases ATM, CHK1, and CHK2 that phosphorylate p53 at Ser and

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