[Georges] Thibout, [Louis] Lajarrige, [Constant] Pilate, députés de Paris : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 56972

Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics.

Alterations of the p53 pathway are among the most frequent aberrations observed in human cancers. We have performed an exhaustive analysis of TP53, p14, p15, and p16 status in a large series of 143 soft tissue sarcomas, rare tumors accounting for around 1% of all adult cancers, with complex genetics. For this purpose, we performed genomic studies, combining sequencing, copy number assessment, and expression analyses. TP53 mutations and deletions are more frequent in leiomyosarcomas than in undifferentiated pleomorphic sarcomas. Moreover, 50% of leiomyosarcomas present TP53 biallelic inactivation, whereas most undifferentiated pleomorphic sarcomas retain one wild-type TP53 allele (87.2%). The spectrum of mutations between these two groups of sarcomas is different, particularly with a higher rate of complex mutations in undifferentiated pleomorphic sarcomas. Most tumors without TP53 alteration exhibit a deletion of p14 and/or lack of mRNA expression, suggesting that p14 loss could be an alternative genotype for direct TP53 inactivation. Nevertheless, the fact that even in tumors altered for TP53, we could not detect p14 protein suggests that other p14 functions, independent of p53, could be implicated in sarcoma oncogenesis. In addition, both p15 and p16 are frequently codeleted or transcriptionally co-inhibited with p14, essentially in tumors with two wild-type TP53 alleles. Conversely, in TP53-altered tumors, p15 and p16 are well expressed, a feature not incompatible with an oncogenic process.

Light-induced degradation of phyA is promoted by transfer of the photoreceptor into the nucleus.

Higher plants possess multiple members of the phytochrome family of red, far-red light sensors to modulate plant growth and development according to competition from neighbors. The phytochrome family is composed of the light-labile phyA and several light-stable members (phyB-phyE in Arabidopsis). phyA accumulates to high levels in etiolated seedlings and is essential for young seedling establishment under a dense canopy. In photosynthetically active seedlings high levels of phyA counteract the shade avoidance response. phyA levels are maintained low in light-grown plants by a combination of light-dependent repression of PHYA transcription and light-induced proteasome-mediated degradation of the activated photoreceptor. Light-activated phyA is transported from the cytoplasm where it resides in darkness to the nucleus where it is needed for most phytochrome-induced responses. Here we show that phyA is degraded by a proteasome-dependent mechanism both in the cytoplasm and the nucleus. However, phyA degradation is significantly slower in the cytoplasm than in the nucleus. In the nucleus phyA is degraded in a proteasome-dependent mechanism even in its inactive Pr (red light absorbing) form, preventing the accumulation of high levels of nuclear phyA in darkness. Thus, light-induced degradation of phyA is in part controlled by a light-regulated import into the nucleus where the turnover is faster. Although most phyA responses require nuclear phyA it might be useful to maintain phyA in the cytoplasm in its inactive form to allow accumulation of high levels of the light sensor in etiolated seedlings.

Identification of novel elements of the Drosophila blisterome sheds light on potential pathological mechanisms of several human diseases.

Main developmental programs are highly conserved among species of the animal kingdom. Improper execution of these programs often leads to progression of various diseases and disorders. Here we focused on Drosophila wing tissue morphogenesis, a fairly complex developmental program, one of the steps of which - apposition of the dorsal and ventral wing sheets during metamorphosis - is mediated by integrins. Disruption of this apposition leads to wing blistering which serves as an easily screenable phenotype for components regulating this process. By means of RNAi-silencing technique and the blister phenotype as readout, we identify numerous novel proteins potentially involved in wing sheet adhesion. Remarkably, our results reveal not only participants of the integrin-mediated machinery, but also components of other cellular processes, e.g. cell cycle, RNA splicing, and vesicular trafficking. With the use of bioinformatics tools, these data are assembled into a large blisterome network. Analysis of human orthologues of the Drosophila blisterome components shows that many disease-related genes may contribute to cell adhesion implementation, providing hints on possible mechanisms of these human pathologies.