Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D

Castellino, Robert C.; Bortoli, Massimiliano De; Lu, Xiongbin; Moon, Sung; Nguyen, Thuy‐Ai; Shepard, Mark A.; Rao, Pulivarthi H.; Donehower, Lawrence A.; Kim, John Y.H.

doi:10.1007/s11060-007-9470-8

Cited by 123 publications

(109 citation statements)

References 32 publications

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“…1A). Wip1 is amplified in various human cancers (22)(23)(24)(25) overexpress the phosphatase (22). In line with the data obtained in the A549 cell lines, treatment with doxorubicin resulted in increased Wip1 protein at 24 h, then followed by a progressive decrease under the base line (Fig.…”

Section: Decrease In Wip1 Protein Level During Premature Senescence-supporting

confidence: 84%

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Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Crescenzi

Raia

Pacifico

et al. 2013

Journal of Biological Chemistry

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Background: Wip1 is a phosphatase involved in DNA-damage response. Results: Wip1 expression is down-regulated in premature senescent cancer cells. Failure to down-regulate Wip1 expression results in cell death and polyploidy. Conclusion: Wip1 down-regulation is important for maintenance of permanent cell cycle arrest in premature senescent tumor cells. Significance: These findings improve our understanding of the mechanism by which Wip1 promotes tumor progression.

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Section: Decrease In Wip1 Protein Level During Premature Senescence-supporting

confidence: 84%

“…Wip1 has been shown to be amplified and overexpressed in various human cancers (22)(23)(24)(25). Based on our results, overexpression of Wip1 in cancer cells may result in a selective advantage as cells bypass the G 2 checkpoint, re-enter the cell cycle, and become polyploid, potentially acquiring additional mutation.…”

Section: Discussionsupporting

confidence: 51%

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Crescenzi

Raia

Pacifico

et al. 2013

Journal of Biological Chemistry

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“…However, P53 mutation or amplification of MDM2, which inhibits P53, has been infrequently reported for medulloblastoma (20,(43)(44)(45)(46). However, PPM1D, shown to inhibit P53 in medulloblastoma, is highly overexpressed in most medulloblastoma and even amplified in some (9,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt

Haas

Hasselt

et al. 2010

Molecular Cancer Research

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The transcription factor orthodenticle homeobox 2 (OTX2) has been implicated in the pathogenesis of medulloblastoma, as it is often highly expressed and sometimes amplified in these tumors. Little is known of the downstream pathways regulated by OTX2. We therefore generated MED8A and DAOY medulloblastoma cell lines with doxycycline-inducible OTX2 expression. In both cell lines, OTX2 inhibited proliferation and induced a senescencelike phenotype with senescence-associated β-galactosidase activity. Expression profiles of time series after OTX2 induction in MED8A showed early upregulation of cell cycle genes related to the G 2 -M phase, such as AURKA, CDC25C, and CCNG2. Paradoxically, G 1 -S phase genes such as MYC, CDK4, CDK6, CCND1, and CCND2 were strongly downregulated, in line with the observed G 1 arrest. ChIP-on-chip analyses of OTX2 binding to promoter regions in MED8A and DAOY showed a strong enrichment for binding to the G 2 -M genes, suggesting a direct activation. Their mRNA expression correlated with OTX2 expression in primary tumors, underscoring the in vivo relevance of this regulation. OTX2 induction activated the P53 pathway in MED8A, but not in DAOY, which carries a mutated P53 gene. In DAOY cells, senescence-associated secretory factors, such as interleukin-6 and insulin-like growth factor binding protein 7, were strongly upregulated after OTX2 induction. We hypothesize that the imbalance in cell cycle stimulation by OTX2 leads to cellular senescence either by activating the P53 pathway or through the induction of secretory factors. Our data indicate that OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle.

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“…105 Similarly, PPM1D has been blamed as the culprit oncogene behind gain or amplification of 17q23 in breast cancer, [106][107][108] ovarian clear cell adenocarcinoma, 109 and medulloblastoma. 110,111 The protein encoded by PPM1D is a serine/threonine phosphatase that is transcriptionally induced by wild-type p53 in response to DNA-damaging stimuli such as ionizing radiation, and it has, therefore, been given the name Wip1 (wild-type p53-induced phosphatase 1). 112 The p53-dependent expression of Wip1 creates a negative feedback loop that helps to turn off p53 at the end of a stress response, as Wip1 suppresses p53 activity and stability through multiple mechanisms (Figures 3a-c).…”

Section: Deregulation Of the P14 Arf -Mdm2-p53 Axis By Ppm1d (Wip1)mentioning

confidence: 99%

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

et al. 2009

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A primary failsafe program against unrestrained proliferation and oncogenesis is provided by the p53 tumor suppressor protein, inactivation of which is considered as a hallmark of cancer. Intriguingly, mutations of the TP53 gene are rarely encountered in neuroblastoma tumors, suggesting that alternative p53-inactivating lesions account for escape from p53 control in this childhood malignancy. Several recent studies have shed light on the mechanisms by which neuroblastoma cells circumvent the p53-driven antitumor barrier. We review here these mechanisms for evasion of p53-mediated growth control and conclude that deregulation of the p14 ARF -MDM2-p53 axis seems to be the principal mode of p53 inactivation in neuroblastoma, opening new perspectives for targeted therapeutic intervention. The p53 tumor surveillance network constitutes the core defense mechanism of the cell against loss of genomic integrity and malignant transformation. Evasion of p53 activity is, therefore, a prerequisite for tumor cells to survive and thrive, and this is attainable either through mutation of the TP53 gene or through defects in the molecular components that govern or execute the various aspects of the p53 response. Elucidation of the mechanisms by which tumor cells override the p53-orchestrated failsafe program is not only important to gain insight into the ontogenesis of a tumor, but may also point to preferable modes of therapeutic intervention.A striking feature of the childhood cancer neuroblastoma is the low frequency (o2%) of TP53 mutations at diagnosis. 1 There is considerable evidence that TP53 mutations may be acquired during chemotherapy and malignant progression of neuroblastoma. 1-4 Accordingly, an increased frequency of TP53 mutations is observed in multidrug-resistant neuroblastoma cell lines and in neuroblastoma cell lines established at relapse, but even in this context, the majority of cell lines remain characterized by a wild-type TP53 gene. 5,6 Furthermore, many studies indicate that the p53 signal transduction pathway is intrinsically intact in neuroblastoma, 1,4,7-9 suggesting that circumvention of the p53 barrier in this tumor entity relies primarily on an inappropriately increased activity of inhibitors of p53 signaling or, alternatively, on a loss of positive regulators of p53 activity. This review summarizes our current understanding of the mechanisms by which neuroblastoma cells escape from p53-mediated tumor surveillance and positions deregulation of the p14 ARF -MDM2-p53 axis as a central switch for p53 inactivation in neuroblastoma.The p14 ARF -MDM2-p53 Axis and Lesions at the MDM2 and CDKN2A (p16 INK4a /p14 ARF ) Loci in NeuroblastomaThe MDM2 oncoprotein, a human homolog of the 'mouse double minute 2' gene product that was originally identified in a spontaneously transformed mouse cell line with double minute chromosomes, 10 is a critical negative regulator of p53 stability and activity. It has been well established that p53 and MDM2 mutually control their cellular levels and form a tight autoregulatory...

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Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D

Cited by 123 publications

References 32 publications

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

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