p8 is critical for tumour development induced by ras<sup>V12</sup> mutated protein and E1A oncogene

Vasseur, Sophie; Hoffmeister, Albrecht; García, Stéphane; Bagnis, Claude; Dagorn, Jean–Charles; Iovanna, Juan

doi:10.1093/embo-reports/kvf023

Cited by 70 publications

(73 citation statements)

References 14 publications

(21 reference statements)

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“…Endogenous p53 represses DJ-1 in a cell-type independent manner. (a-c) Wild-type, p53 À/À and DNp73 À/À primary or immortalized MEFs were derived from gene-targeted C57BL6/J background mice and their littermates as previously described (Vasseur et al, 2002;Wilhelm et al, 2010). Transformed MEFs were obtained by transduction with the E1A and RasV12 oncogenes using retroviral infection (pLPC-E1A-IRES-RasV12) and selected by growth in puromycin.…”

Section: Resultsmentioning

confidence: 99%

Consequences of DJ-1 upregulation following p53 loss and cell transformation

et al. 2011

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p53 is a tumor suppressor that responds to various stress signals by initiating cell-cycle arrest, senescence and apoptosis. Mutations of the p53 gene are found in over 50% of human tumors, highlighting the importance of p53 in tumor suppression. Numerous studies have reported on the interactions between p53, IGF-1-AKT and mTOR pathways as potentially explaining some of the tumor suppressive activities of p53. To further understand the basis of these interactions, we analyzed the involvement of DJ-1, an oncogene known to drive AKT-mediated cell survival, in the p53-AKT axis. In this study, we show that DJ-1 and p53 are tightly 'linked': p53 prevents the accumulation of DJ-1 protein, whereas loss of p53 leads to stabilization and enhancement of DJ-1 expression. Interestingly, this increase in DJ-1 level is only observed when p53 loss is accompanied by transformation of cells. Moreover, DJ-1 seems to be required for the enhanced activation of AKT observed in p53-deficient cells. Such observation confers a new property to DJ-1 associated to transforming-process to its oncogenic ability to drive AKT activation. We also show that DJ-1 is necessary for p53 activation following oxidative stress, suggesting the existence of a finely regulated loop between these two proteins in transformed cells. Finally, we demonstrate that in the absence of p53, DJ-1 is stabilized by ROS accumulation, and surprisingly seems to be required for this high intracellular ROS production. These data offer new insights into the regulation of DJ-1 and suggest that DJ-1 is a target of p53. Importantly, our study highlights that during transformation, DJ-1 is having a key role in the p53-regulated AKT pathway and p53-driven oxidative-stress response.

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Section: Resultsmentioning

confidence: 99%

Consequences of DJ-1 upregulation following p53 loss and cell transformation

et al. 2011

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“…In breast cancer cells, the rising expression of Com-1 is thought to be responsible to 1,25-dihydroxyvitamin D3-induced growth reduction. 7 In fibroblasts, p8 is a cell growth inhibitor that facilitates apoptosis induced in fibroblasts by DNA damage, 9 which may involve p53. It has been further shown that transfection of pancreatic cancer cells with Com-1/ p8 resulted in growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…pBabe-rasV12/E1A transformed mouse embryo fibroblasts, when overexpressed Com1/p8 became tumourigenic in a mouse model, however the same fibroblast without p8 expression failed to form tumours. 7 There have been some controversial reports to indicate a different role of Com-1 in cancer cells and possibly in clinical cancer. In breast cancer cells, for example, levels of Com-1 were associated with growth inhibition by 1,25-dihydroxyvitamin D3.…”

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confidence: 99%

Expression of Com‐1/P8 in human breast cancer and its relevance to clinical outcome and ER status

Jiang

Watkins

Douglas-Jones

et al. 2005

Intl Journal of Cancer

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Com‐1 is a recently discovered molecule that has putative action on the metastatic nature of cancer cells. The molecular action and clinical implication in cancer and prognosis are yet to be established. The current study examined the role of Com‐1 in a cohort of patients with breast cancer, with particular emphasis on its relationship with clinical outcomes and ER status. A panel of human breast cancer cell lines were tested. A cohort of breast cancer tumours (n‐120) with matched normal non‐neoplastic mammary tissues (n = 32) were used. Expression of Com‐1 in cancer cells and mammary tissues were studied using conventional and real‐time quantitative PCR. Expression profile was analysed against clinical information including tumour grade, staging, nodal status, ER status and survival of the patients. Statistical analysis was Mann‐Whitney U‐test and Cox Proportion analysis. Com‐1 was expressed in breast cancer cell lines. Com‐1 protein staining was primarily found in nucleus of epithelial cells of mammary tissues. Tumour cells in breast tissues exhibited a significant reduction in nuclear staining of Com‐1, compared to normal epithelial cells (p = 0.0061). Breast tumour tissues expressed similar levels of Com‐1, compared to normal non‐neoplastic mammary tissues (p = 0.62). There was, however, a stepwise decrease in tumours from patients with predicted good, moderate, to poor prognosis (using Nottingham Prognostic Index) (166 ± 135 copies of Com1 transcript, 44.3 ± 36 and 0.64 ± 0.24, respectively, p = 0.06 by Kruskal‐Wallis test). Likewise, node positive tumours had low levels of Com‐1, compared to node negative tumours. Tumours from patients who developed metastasis (11.4 ± 7 copies of Com1 transcript), had local recurrence (41.5 ± 3.7 copies of Com1 transcript), or who died of breast cancer (0.058 ± 0.03 copies of Com1 transcript) had lower levels of Com‐1, when compared to tumours from patients who remained disease free (156 ± 129 copies of Com1 transcript). There was no significant correlation between Com‐1 and overall survival or disease free survival. When ER status were taken into consideration, it was demonstrated that low levels of Com‐1 in ER‐β positive tumours were highly correlated with shorter overall survival of the patients (p = 0.018) (median follow‐up 120 months). Com‐1 is a nuclear protein, whose expression is reduced in human breast cancer tissues and cancer cell lines. The loss of Com‐1 protein is primarily from the nuclear compartment in cancer cells. The expression levels of Com‐1 in breast tumours are correlated with the prognosis of the patients and with the long term overall survival in association with ER status. © 2005 Wiley‐Liss, Inc.

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“…Indeed, p8 is known to be crucial for tumor development and involved in the development of pancreatic as well as other human cancers. 34,35 So far, mechanisms related to CCK2 receptor activation that are responsible of p8 expression in ElasCCK2 pancreas are still unknown but worth further specific investigation.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Mathieu

Clerc

Portolan

et al. 2005

Intl Journal of Cancer

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In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: G protein coupled receptors; CCK2 receptor; precancerous conditions; gastrin; transdifferentiation; experimental animal model; developmental gene Peptides of the cholecystokinin (CCK)/gastrin family are present in the gastrointestinal tract where they are known to physiologically regulate gallbladder and bowel motility, pancreatic and gastric secretion as well as growth and trophicity of gastrointestinal epithelial mucosa. 1 Two receptors that mediate the actions of cholecystokinin and gastrin have been pharmacologically classified as CCK1 and CCK2 receptors on the basis of their binding affinity for their natural ligands. While the CCK1 receptor is highly selective towards cholecystokinin vs. gastrin, the CCK2 receptor binds the 2 agonists with similar high affinities. 2 Both are G-protein coupled receptors with extrinsic tyrosine kinase activity. They activate many intracellular mediators classically described in the regulation of mitogenesis by growth factors. 3 Mitogen-activated protein kinases, ERK1/2, Jun kinase and p38MAPK, as well as the phosphatidylinositol 3-kinase (PI3K) and early responsive genes (c-fos, c-myc and c-jun), are known targets of gastrin. 4-7 Several groups including ours, have documented the contribution of Src and focal adhesion kinase (Fak) families' tyrosine kinases upstream the activation of these pathways. 4,8 The role of gastrin and CCK2 receptors as positive regulators of proliferation of normal...

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p8 is critical for tumour development induced by ras^V12 mutated protein and E1A oncogene

Cited by 70 publications

References 14 publications

Consequences of DJ-1 upregulation following p53 loss and cell transformation

Consequences of DJ-1 upregulation following p53 loss and cell transformation

Expression of Com‐1/P8 in human breast cancer and its relevance to clinical outcome and ER status

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

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p8 is critical for tumour development induced by rasV12 mutated protein and E1A oncogene

Cited by 70 publications

References 14 publications

Consequences of DJ-1 upregulation following p53 loss and cell transformation

Consequences of DJ-1 upregulation following p53 loss and cell transformation

Expression of Com‐1/P8 in human breast cancer and its relevance to clinical outcome and ER status

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

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p8 is critical for tumour development induced by ras^V12 mutated protein and E1A oncogene