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The transcription factor E2F1 has a crucial role in the control of cell growth and has been shown to regulate neoangiogenesis in a p53-dependent manner through inhibition of activity of the VEGF-A (vascular endothelial growth factor) promoter. Besides being regulated by transcription, VEGF-A is also highly regulated by pre-mRNA alternative splicing, resulting in the expression of several VEGF isoforms with either pro-(VEGF xxx ) or anti-(VEGF xxx b) angiogenic properties. Recently, we identified the SR (Ser-Rich/Arg) protein SC35, a splicing factor, as a new transcriptional target of E2F1. Here, we show that E2F1 downregulates the activity of the VEGF-A promoter in tumour cells independently of p53, leading to a strong decrease in VEGF xxx mRNA levels. We further show that, strikingly, E2F1 alters the ratio of pro-VEGF xxx versus anti-VEGF xxx b angiogenic isoforms, favouring the antiangiogenic isoforms, by a mechanism involving the induction of SC35 expression. Finally, using lung tumour xenografts in nude mice, we provide evidence that E2F1 and SC35 proteins increase the VEGF 165 b/VEGF ratio and decrease tumour neovascularization in vivo . Overall, these findings highlight E2F1 and SC35 as two regulators of the VEGF xxx /VEGF xxx b angiogenic switch in human cancer cells, a role that could be crucial during tumour progression, as well as in tumour response to antiangiogenic therapies.

The transcription factor E2F1 has a key function during S phase progression and apoptosis. It has been well-demonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Alternative splicing of pre-mRNAs also has an important function in the regulation of apoptosis. In this study, we identify the splicing factor SC35, a member of the Ser-Rich Arg (SR) proteins family, as a new transcriptional target of E2F1. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip , caspases-8 and - 9 and Bcl-x , towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. Taken together, these results demonstrate that E2F1 controls pre-mRNA processing events to induce apoptosis and identify the SC35 SR protein as a key direct E2F1-target in this setting.

The transcription factor E2F-1 plays a crucial role in the control of cellular growth. We previously reported its differential pattern of expression in human lung tumors. In this study, we have investigated the relationships linking the status of E2F-1 and a mediator of its proteasomal degradation, the S-phase kinase-associated protein 2 (Skp2) F-box protein. Using immunohistochemistry in a series of 129 lung tumors of all histological types, we demonstrate that Skp2 accumulates preferentially in high-grade neuroendocrine (HGNE) lung carcinomas (86%, P <0.0001), and show that Skp2 overexpression is associated with advanced stages ( P <0.0001) and nodal metastasis ( P <0.0001) in neuroendocrine (NE) lung tumors. Unexpectedly, we observe that Skp2 and E2F-1 expression directly correlates in NE lung tumors ( P <0.0001). Moreover, using cellular models, we identify Skp2 as a new E2F-1 transcriptional target. Furthermore, we also provide evidence that Skp2 interacts physiologically with E2F-1 and stimulates its transcriptional activity toward the cyclin E promoter. Consistently, we demonstrate that cyclin E expression directly correlates with Skp2 ( P <0.0001) and E2F-1 ( P =0.0001) status in NE lung tumors. Overall, our data provide the first evidence of a direct and functional interconnection between the E2F-1, Skp2 and cyclin E oncoproteins in HGNE lung carcinomas.

The three-dimensional composition profiles of individual SiGe/Si(001) islands grown on planar and pit-patterned substrates are determined by atomic force microscopy (AFM)-based nanotomography. The observed differences in lateral and vertical composition gradients are correlated with the island morphology. This approach allowed us to employ AFM to simultaneously gather information on the composition and strain of SiGe islands. Our quantitative analysis demonstrates that for islands with a fixed aspect ratio, a modified geometry of the substrate provides an enhancement of the relaxation, finally leading to a reduced intermixing.

We investigate the effect of strain on the etching rate of two SiGe wet etchants, namely NH4OH:H2O2 and H2O2. For both etchants, we found that there is no appreciable strain selectivity, i.e. the etching rates do not depend on the actual strain state in the SiGe films. Instead, for the NH4OH:H2O2 solution, the rates are primarily determined by the Ge content. Finally, we show that both etchants are isotropic with no preferential etching of particular facets.