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Furlan A.,Institut Universitaire de France | Stagni V.,Laboratory of Cell Signaling | Stagni V.,University of Rome Tor Vergata | Hussain A.,Institut Universitaire de France | And 9 more authors.
Cell Death and Differentiation

The simplicity of BCR-ABL oncogene addiction characterizing leukemia contrasts with the complexity of solid tumors where multiple core pathways, including receptor tyrosine kinases (RTKs) and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared with the impact of Imatinib in BCR-ABL-dependent leukemia. Here, we identified c-Abl as a signaling node interconnecting Met-RTK and p53 core pathways, and showed that its inhibition impairs Met-dependent tumorigenesis. Met ensures cell survival through a new path in which c-Abl and p38-MAPK are employed to elicit p53 phosphorylation on Ser 392 and Mdm2 upregulation. We found a clinical correlation between activated Met, phospho-p53, and Mdm2 levels in human tumors, supporting the role of this path in tumorigenesis. Our findings introduce the concept that RTK-driven tumors may be therapeutically treated by hitting signaling nodes interconnecting core pathways. Moreover, they underline the importance of evaluating the relevance of c-Abl antagonists for combined therapies, based on the tumor signaling signature. © 2011 Macmillan Publishers Limited All rights reserved. Source

Gilardini Montani M.S.,University of Tuscia | Prodosmo A.,Regina Elena Cancer Institute | Stagni V.,Laboratory of Cell Signaling | Stagni V.,University of Rome Tor Vergata | And 7 more authors.
Journal of Experimental and Clinical Cancer Research

Background: Mutations in the DNA damage response (DDR) factors, breast cancer 1 (BRCA1) and BRCA2, sensitize tumor cells to poly(ADP-ribose) polymerase (PARP) inhibitors. The ataxia telangiectasia mutated (ATM) kinase is a key DDR protein whose heterozygous germline mutation is a moderate-risk factor for developing breast cancer. In this study, we examined whether ATM inactivation in breast cancer cell lines confers sensitivity to PARP inhibitors. Methods. Wild-type BRCA1/2 breast cancer cells (i.e., MCF-7 and ZR-75-1 lines) were genetically manipulated to downregulate ATM expression then assayed for cytostaticity/cytotoxicity upon treatment with PARP inhibitors, olaparib and iniparib. Results: When ATM-depleted cells and their relative controls were treated with olaparib (a competitive PARP-1/2 inhibitor) and iniparib (a molecule originally described as a covalent PARP-1 inhibitor) a different response to the two compounds was observed. ATM-depletion sensitized both MCF-7 and ZR-75-1 cells to olaparib-treatment, as assessed by short and long survival assays and cell cycle profiles. In contrast, iniparib induced only a mild, ATM-dependent cytostatic effect in MCF-7 cells whereas ZR-75-1 cells were sensitive to this drug, independently of ATM inactivation. These latest results might be explained by recent observations indicating that iniparib acts with mechanisms other than PARP inhibition. Conclusions: These data indicate that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers. © 2013 Gilardini Montani et al.; licensee BioMed Central Ltd. Source

Stagni V.,Laboratory of Cell Signaling | Stagni V.,University of Rome Tor Vergata | Manni I.,Regina Elena Cancer Institute | Oropallo V.,Laboratory of Cell Signaling | And 12 more authors.
Nature Communications

ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATMâ €™ s tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor © 2015 Macmillan Publishers Limited. All rights reserved. Source

Santini S.,University of Rome Tor Vergata | Santini S.,Laboratory of Cell Signaling | Stagni V.,University of Rome Tor Vergata | Stagni V.,Laboratory of Cell Signaling | And 8 more authors.

Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response, regulates the activity of several E3-ubiquitin ligases, and the ubiquitination-proteasome system is a consistent target of ATM. ITCH is an E3-ubiquitin ligase that modulates the ubiquitination of several targets, therefore participating to the regulation of several cellular responses, such as the DNA damage response, tumor necrosis factorα (TNFα), Notch and Hedgehog signaling, and the differentiation of 'naive' lymphocytes into T helper type 2 cells. Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. ATM activity enhances ITCH enzymatic activity, which in turn drives the ubiquitination and degradation of c-FLIP-L and c-Jun, previously identified as ITCH substrates. Importantly, ATM-deficient mice show resistance to hepatocyte cell death, similarly to Itch-deficient animals, providing in vivo genetic evidence for this circuit. Our data identify ITCH as a novel component of the ATM-dependent signaling pathway and suggest that the impairment of the correct functionality of ITCH caused by Atm deficiency may contribute to the complex clinical features linked to Ataxia Telangiectasia. © 2014 Macmillan Publishers Limited. Source

Mongiardi M.P.,CNR Institute of Neuroscience | Stagni V.,University of Rome Tor Vergata | Stagni V.,Laboratory of Cell Signaling | Natoli M.,CNR Institute of Neuroscience | And 7 more authors.
Cell Cycle

The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cell adaptation to decreasing oxygen levels. High oxygen tension promotes proteasomal degradation of HIF-1α via a pathway that requires hydroxylation of prolines 402 and 564. Low oxygen tension, hypoxia, inactivates the hydroxylases responsible for these modifications through a mechanism that is not fully understood but appears to require mitochondrial respiration and production of Reactive Oxygen Species, ROS. Cells from individuals affected by ataxia telangiectasia syndrome have an impaired mitochondrial activity and a constitutive oxidative stress. Here we show that, in these cells, HIF-1α is efficiently degraded even in condition of low oxygen tension. Mechanistically this depends from a blunted increase in intracellular concentration of ROS in response to hypoxia which in turn is due to an increased cellular capacity of buffering ROS. We suggest that regulation of HIF-1α stability may depend on fold chance of ROS relative to the basal level more than on their absolute value. Since elevated oxidative stress is a hallmark of many human disorders our finding may be relevant to different pathologies. © 2011 Landes Bioscience. Source

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