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De Cola A.,University of Rome Tor Vergata | Bongiorno-Borbone L.,University of Rome Tor Vergata | Bianchi E.,University of Rome Tor Vergata | Bianchi E.,Laboratory of Neuroembryology | And 11 more authors.
Oncogene | Year: 2012

Replication-dependent histone gene expression is a fundamental process occurring in S-phase under the control of the cyclin-E/CDK2 complex. This process is regulated by a number of proteins, including Flice-Associated Huge Protein (FLASH) (CASP8AP2), concentrated in specific nuclear organelles known as HLBs. FLASH regulates both histone gene transcription and mRNA maturation, and its downregulation in vitro results in the depletion of the histone pull and cell-cycle arrest in S-phase. Here we show that the transcription factor p73 binds to FLASH and is part of the complex that regulates histone gene transcription. Moreover, we created a novel gene trap to disrupt FLASH in mice, and we show that homozygous deletion of FLASH results in early embryonic lethality, owing to arrest of FLASH -/- embryos at the morula stage. These results indicate that FLASH is an essential, non-redundant regulator of histone transcription and cell cycle during embryogenesis. © 2012 Macmillan Publishers Limited All rights reserved.

Allocati N.,University of Chieti Pescara | Di Ilio C.,University of Chieti Pescara | Di Ilio C.,Centro Studi sullInvecchiamento | De Laurenzi V.,University of Chieti Pescara | And 2 more authors.
Experimental Cell Research | Year: 2012

The p53 family apparently derives from a common ancient ancestor that dates back over a billion years, whose function was protecting the germ line from DNA damage. p63 and p73 would maintain this function through evolution while acquiring novel roles in controlling proliferation and differentiation of various tissues. p53 on the other hand would appear in early vertebrates to protect somatic cells from DNA damage with similar mechanism used by its siblings to protect germ line cells . [1]. For the predominant role played by p53 mutations in cancer this was the first family member to be identified and soon became one of the most studied genes. Its siblings were identified almost 20. years later and interestingly enough their ancestral function as guardians of the germ-line was one of the last to be identified. In this review we shortly summarize the current knowledge on the structure and function of p63 and p73. © 2012 Elsevier Inc.

Favaloro B.,University of Chieti Pescara | Favaloro B.,Centro Studi sullInvecchiamento | Allocati N.,University of Chieti Pescara | Graziano V.,University of Chieti Pescara | And 6 more authors.
Aging | Year: 2012

Since the initial description of apoptosis, a number of different forms of cell death have been described. In this review we will focus on classic caspase-dependent apoptosis and its variations that contribute to diseases. Over fifty years of research have clarified molecular mechanisms involved in apoptotic signaling as well and shown that alterations of these pathways lead to human diseases. Indeed both reduced and increased apoptosis can result in pathology.More recently these findings have led to the development of therapeutic approaches based on regulation of apoptosis, some of which are in clinical trials or have entered medical practice. © Favaloro al.

De Luca A.,Centro Studi sullInvecchiamento | De Luca A.,University of Chieti Pescara | Sanna F.,Centro Studi sullInvecchiamento | Sanna F.,University of Chieti Pescara | And 11 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Breast cancer is one of the most frequent of human malignacies, and it is therefore fundamental to identify the underlying molecular mechanisms leading to cancer transformation. Among other causative agents in the development of breast cancers, an important role for reactive oxygen species (ROS) has emerged. However, most studies on the role of ROS in cancer have not reached specific conclusions, and many issues remain controversial. In the present study, we show that methionine sulfoxide reductase A (MsrA), which is known to protect proteins from oxidation and which acts as a ROS scavenger, is down-regulated in a number of breast cancers. Moreover, levels of MsrA correlate with advanced tumor grade. We therefore investigated the functional role of MsrA in breast cancer cells. Our data show that reduction of MsrA levels results in increased cell proliferation and extracellular matrix degradation, and consequently in a more aggressive cellular phenotype, both in vivo and in vitro. We also show that the underlying molecular mechanisms involve increased ROS levels, resulting in reduction of phosphatase and tensin homolog deleted on chromosome ten protein (PTEN), and activation of the phosphoinositide 3-kinase pathway. In addition, MsrA down-regulation results in up-regulation of VEGF, providing additional support for tumor growth in vivo.

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