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

Demidov, Oleg N.; Kek, Calvina; Shreeram, Sathyavageeswaran; Timofeev, Oleg; Fornace, Albert J.; Appella, Ettore; Bulavin, Dmitry V.

doi:10.1038/sj.onc.1210032

Cited by 97 publications

(86 citation statements)

References 18 publications

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“…This observation has led to the hypotheses that PPM1D overexpression is a causative factor in tumorigenesis and that inhibition of PPM1D may be of therapeutic benefit. However, validation of PPM1D as a therapeutic target in cancer has focused on the reduction of normal Ppm1d levels in the mouse using gene targeting (Bulavin et al, 2004;Nannenga et al, 2006) or, in one instance, transgenic overexpression of PPM1D in the mouse breast epithelium (Demidov et al, 2007). The proposed model of PPM1D involvement in cancer involves overexpression in human tissue and, therefore, an important proof-of-principle experiment is to show that inhibition of aberrantly elevated, but not basal, levels of PPM1D can be selectively lethal in human tumour cells.…”

Section: Resultsmentioning

confidence: 99%

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

et al. 2007

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The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor.

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Section: Resultsmentioning

confidence: 99%

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

et al. 2007

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“…INK4a levels are increased and the mice are protected from the early onset of mammary tumors in response to Ras, Neu and ErbB2 oncogenes Demidov et al, 2006). The addition of a pharmacological inhibitor of p38 activity to the Wip1-null mice reduced p16…”

Section: Role Of P38 In Cancermentioning

confidence: 99%

“…INK4a expression and led to the formation of mammary tumors , whereas mice bearing a constitutively active form of the p38 activator MKK6 suppressed the tumor-prone phenotype of mice overexpressing Wip1 in mammary epithelium (Demidov et al, 2006).…”

Section: Role Of P38 In Cancermentioning

confidence: 99%

Role of mitogen-activated protein kinase kinase 4 in cancer

2007

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“…105,[107][108][109][110] Overexpression experiments have shown that Wip1 induces malignant transformation in collaboration with other oncogenes, protects against oncogene-induced premature senescence and apoptosis, and accelerates tumorigenesis in vivo. 106,107,123,124 Conversely, Ppm1d-null MEFs and mice are resistant to oncogene-induced transformation and to spontaneous and oncogene-driven tumorigenesis, respectively. 119,122,123 Although most of the oncogenic properties of Wip1 are ascribed to its ability to suppress the p53 pathway and the DNA damage response, concomitant inhibition of pRb tumor suppressor activity because of transcriptional repression of p16 INK4a expression may also play a role.…”

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

Cited by 97 publications

References 18 publications

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

Role of mitogen-activated protein kinase kinase 4 in cancer

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

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