COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ.

14-3-3σ, a gene upregulated by p53 in response to DNA damage, exists as part of a positive-feedback loop, which activates p53 and is a human cancer epithelial marker downregulated in various cancer types. 14-3-3σ levels are critical for maintaining p53 activity in response to DNA damage and regulating signal mediators such as Akt. In this study, we identify mammalian constitutive photomorphogenic 1 (COP1) as a novel E3 ubiquitin ligase for targeting 14-3-3σ through proteasomal degradation. We show for the first time that COP9 signalosome subunit 6 (CSN6) associates with COP1 and is involved in 14-3-3σ ubiquitin-mediated degradation. Mechanistic studies show that CSN6 expression leads to stabilization of COP1 through reducing COP1 self-ubiquitination and decelerating COP1's turnover rate. We also show that CSN6-mediated 14-3-3σ ubiquitination is compromised when COP1 is knocked down. Thus, CSN6 mediates 14-3-3σ ubiquitination through enhancing COP1 stability. Subsequently, we show that CSN6 causes 14-3-3σ downregulation, thereby activating Akt and promoting cell survival. Also, CSN6 overexpression leads to increased cell growth, transformation and promotes tumorigenicity. Significantly, 14-3-3σ expression can correct the abnormalities mediated by CSN6 expression. These data suggest that the CSN6-COP1 axis is involved in 14-3-3σ degradation, and that deregulation of this axis will promote cell growth and tumorigenicity.

Pim-1 plays a pivotal role in hypoxia-induced chemoresistance.

Hypoxia changes the responses of cancer cells to many chemotherapy agents, resulting in chemoresistance. The underlying molecular mechanism of hypoxia-induced drug resistance remains unclear. Pim-1 is a survival kinase, which phosphorylates Bad at serine 112 to antagonize drug-induced apoptosis. Here we show that hypoxia increases Pim-1 in a hypoxia-inducible factor-1alpha-independent manner. Inhibition of Pim-1 function by dominant-negative Pim-1 dramatically restores the drug sensitivity to apoptosis induced by chemotherapy under hypoxic conditions in both in vitro and in vivo tumor models. Introduction of siRNAs for Pim-1 also resensitizes cancer cells to chemotherapy drugs under hypoxic conditions, whereas forced overexpression of Pim-1 endows solid tumor cells with resistance to cisplatin, even under normoxia. Dominant-negative Pim-1 prevents a decrease in mitochondrial transmembrane potential in solid tumor cells, which is normally induced by cisplatin (CDDP), followed by the reduced activity of Caspase-3 and Caspase-9, indicating that Pim-1 participates in hypoxia-induced drug resistance through the stabilization of mitochondrial transmembrane potential. Our results demonstrate that Pim-1 is a pivotal regulator involved in hypoxia-induced chemoresistance. Targeting Pim-1 may improve the chemotherapeutic strategy for solid tumors.

Expression of platelet-derived growth factor receptor in low-grade endometrial stromal sarcomas in the absence of activating mutations.

AIMS: To investigate platelet-derived growth factor receptor (PDGFR)alpha and PDGFRbeta expression and a mutational analysis of PDGFRalpha (exons 11, 12, 17 and 18) and PDGFRbeta (exon 12) genes in endometrial stromal sarcomas (ESS). Gastrointestinal stromal tumours (GISTs), which have somatic mutations of the transmembrane tyrosine kinase receptor, respond to tyrosine kinase inhibitors, which act through an inhibitory effect on class 3 receptor tyrosine kinase members such as PDGFRalpha, PDGFRbeta and c-kit. METHODS AND RESULTS: The immunohistochemical expression of PDGFRalpha and PDGFRbeta was investigated in 37 archival c-kit- ESS. Staining was scored as negative (0-10% positive tumour cells) and positive (weakly positive 11-50% positive cells; strongly positive > 50% positive cells). PDGFRalpha was expressed in 24/37 ESS [65%; strongly by 19/37 (51.5%) and weakly by 5/37 ESS (13.5%)]. ESS tumour cells were negative for PDGFRbeta, but endothelial cells stained positive. A mutational analysis of PDGFRalpha (exons 11, 12, 17 and 18) and PDGFRbeta (exon 12) genes on frozen metastatic ESS from three patients detected no mutations leading to amino acid changes in the mature protein. CONCLUSIONS: Patients with PDGFRalpha+ ESS may benefit from treatment with tyrosine kinase inhibitors by blocking autocrine and paracrine stimulation loops, blocking neovascularization and enhancing the effects of chemotherapy.

[Right atrial intracardiac varices. Review of the literature and case report]. / Varices intracardiaques auriculaires droites. Revue de la littérature à propos d'une observation.

Right atrial varices are rare. They were described for the first time by anatomo-pathologists at the end of the 19th century and beginning of the 20th century. They are situated in the lower part of the inter-atrial septum and rarely exceed 2 cm in diameter. Descriptions have been from post-mortem studies which have led to epidemiological analyses and have given rise to nosological controversies. The authors report a case characterised by the exceptional volume of the varices. This could have enabled the diagnosis to be suspected at transoesophageal echocardiography before surgery. Thoracic CT scan and MRI completed the iconography. In the literature, two other cases of cardiac varices diagnosed at echocardiography have been published: they were small tumours on the lower part of the interatrial septum and the diagnosis before surgery was that of a myxoma. These formations seem to correspond to chance findings and do not appear to give rise to symptoms.

[Clinical expression of papillary fibroelastoma. Apropos of a case]. / Expressions cliniques des fibro-élastomes papillaires. A propos d'une observation.

The authors review the literature of the clinical features of papillary fibroelastomas in the light of a new case. These benign tumours of the endocardium may be distinguished from Lambl's vegetations by their site and size. Some workers suggest that they correspond to giant Lambl's vegetation and could be a form of "aging" of the valvular endocardium. Nevertheless, Lambl's vegetations are always present after 10 years of age but the papillary fibroelastoma is rarely detected by echocardiography and there have been few case reports. They are essentially cardiac valve tumours (73% of valvular tumours) and may give rise to serious clinical symptoms, sudden death by migration or coronary obstruction, systemic embolism, especially from left heart lesions. However, they can be situated at any point of the endocardium. The diagnosis of a valvular or an endocardial tumour is based on echocardiography which, though not always accurate, gives a better aetiological diagnosis. In cases of symptomatic tumours, surgery (usually simple ablation) is indicated with a low operative risk and cure of symptoms. Tumours discovered by chance pose very difficult problems of management and may lead to diagnostic or preventive surgery.