Éditeur(s) : HAL CCSD Taylor & Francis
Résumé : International audience
The retroviral genome consists of an intron-containing transcript that has essential cytoplasmic functions in the infected cell. This viral transcript can escape splicing, circumvent the nuclear checkpoint mechanisms and be transported to the cytoplasm by hijacking the host machinery. Once in the cytoplasm, viral unspliced RNA acts as mRNA to be translated and as genomic RNA to be packaged into nascent viruses. The murine leukemia virus (MLV) is among the first retroviruses discovered and is classified as simple Retroviridae due to its minimal encoding capacity. The oncogenic and transduction abilities of MLV are extensively studied, whereas surprisingly the crucial step of its nuclear export has remained unsolved until 2014. Recent work has revealed the recruitment by MLV of the cellular NXF1/Tap-dependent pathway for export. Unconventionally, MLV uses of Tap to export both spliced and unspliced viral RNAs. Unlike other retroviruses, MLV does not harbor a unique RNA signal for export. Indeed, multiple sequences throughout the MLV genome appear to promote export of the unspliced MLV RNA. We review here the current understanding of the export mechanism and highlight the determinants that influence MLV export. As the molecular mechanism of MLV export is elucidated, we will gain insight into the contribution of the export pathway to the cytoplasmic fate of the viral RNA
ISSN: 1547-6286

hal-01217990
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01217990
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01217990/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01217990/file/Insights%20into%20the%20nuclear%20export%20of%20murine%20leukemia%20virus%20intron-containing%20RNA.pdf
DOI : 10.1080/15476286.2015.1065375

Éditeur(s) : HAL CCSD Impact journals
Résumé : International audience
Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine. We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients. Frequencies of ROS1 and RET rearrangements were 2.1% and 2.52%, respectively. Contrary to common belief, both ROS1 and RET rearrangements were detected in patients with a history of smoking, and the RET-positive patients were not younger than the negative patients. Moreover, RET but not ROS1 rearrangement was associated with the female gender. Nearly half of the ROS1-rearranged patients were successfully treated with ROS1 TKIs. In contrast, only 5/18 RET-positive patients received off-label RET TKIs. Two patients had stable disease, and three experienced disease progression. In addition to the 18 RET-positive cases, 10 showed isolated 5' signals. The clinical relevance is unknown but if the frequency is confirmed by other groups, the question whether these patients are eligible to TKIs will arise. More potent RET TKIs are under development and may improve the response rate in RET-positive patients. Therefore, we recommend the routine implementation of RET testing in non-squamous NSCLC patients, including those with a history of smoking.
ISSN: 1949-2553

hal-01578586
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578586
DOI : 10.18632/oncotarget.18408
PUBMED : 28881815

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells
ISSN: 2045-2322

hal-01165439
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439/file/TP53%20transcription%20factor.pdf
DOI : 10.1038/srep10356

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. The cell functions of cyclin D1 depend on its partners and/or subcellular distribution, resulting in different oncogenic properties. We observed the accumulation of cyclin D1 in the cytoplasm of a subset of MCL cell lines and primary cells. In primary cells, this cytoplasmic distribution was correlated with a more frequent blastoid phenotype. We performed immunoprecipitation assays and mass spectrometry on enriched cytosolic fractions from two cell lines. The cyclin D1 interactome was found to include several factors involved in adhesion, migration and invasion. We found that the accumulation of cyclin D1 in the cytoplasm was associated with higher levels of migration and invasiveness. We also showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Our data reveal a role of cytoplasmic cyclin D1 in the control of MCL cell migration and invasion, and as a true operator of MCL pathogenesis.
ISSN: 2045-2322

hal-01635754
https://hal.archives-ouvertes.fr/hal-01635754
DOI : 10.1038/s41598-017-14222-1
PUBMED : 29066743