ATM kinase activity modulates ITCH E3-ubiquitin ligase activity.

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.

Abl interconnects oncogenic Met and p53 core pathways in cancer cells.

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.

[Magnetic resonance in surgical planning in hepatocarcinomas]. / La risonanza magnetica nella programmazione chirurgica degli epatocarcinomi.

The diagnostic accuracy of Magnetic Resonance Imaging (MRI) in the preoperative staging of unifocal hepatocellular carcinoma (HCC) was investigated and compared with that of ultrasonography (US) and Computed Tomography (CT). Eighteen patients with focal HCCs underwent MRI, CT and US scans before surgery. In all cases the histopathologic diagnosis was made with CT-guided fine-needle aspiration biopsy (FNAB). The diagnostic accuracy of each imaging modality was investigated with the assessment of three parameters thought to be of the utmost importance for surgical planning, i.e., lesion unifocality, the presence of a capsule and finally vascular involvement. MRI proved to be more sensitive than CT in demonstrating both lesion unifocality (100% vs. 94.4%) and the presence of a capsule (100% vs. 71.4%). In 2 of 18 patients some blood vessels were involved, which was clearly demonstrated only by MRI, CT missing it. Both MRI and CT had 100% specificity in the detection of a perilesional capsule and of vascular involvement. To conclude, MRI exhibited higher diagnostic accuracy than US and CT, thus confirming its major role in the preoperative staging of unifocal HCCs.

[Computed tomography in the follow-up of patients nephrectomized for adenocarcinoma]. / La tomografia computerizzata nel controllo dei pazienti nefrectomizzati per adenocarcinoma.

A retrospective study was carried out of 159 CT examinations acquired in 64 patients who underwent unilateral nephrectomy for renal-cell carcinoma (34 in the left-hand side and 30 in the right-hand side). Thirty-nine patients were examined twice in the three years following nephrectomy; 25 were examined three or more times over a 5-year period after nephrectomy. Acute or chronic inflammatory disease was demonstrated in 6 patients (4 abscesses were detected by means of clinico-radiologic signs and 2 by means of cytology after CT-guided needle biopsy). Twenty patients had local recurrences 2-7 cm phi: in 17 of them the diagnosis was confirmed by CT-guided percutaneous FNAB; 15 patients had liver metastases, in 3 of them associated with local recurrences; 26 patients were free of both local recurrences and distant metastases. The authors analyze the value of CT in the definition of post-nephrectomy anatomic alterations, in the early detection and staging of local recurrences, and in the differentiation between postoperative fibrosis and complications. Moreover, the value is stressed of CT-guided FNAB of suspicious lesions. Our study suggests the value of a methodical CT follow-up of asymptomatic post-nephrectomy patients. CT immediately after surgery is also recommended to serve as a baseline reference for subsequent examinations. In our series, CT was accurate in the early detection of both local recurrences and distant solitary metastases.