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NOUVELLES FONCTIONS DE LA PROTEINE E2F1 DANS LE CONTROLE DE L'EPISSAGE DES TRANSCRITS: IMPLICATION DANS LA CARCINOGENESE BRONCHIQUE

Abstract : The transcription factor E2F1 plays a key role during S phase progression and apoptosis. It has been welldemonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Having established a differential pattern of its protein expression in lung tumours, we have studied its potential role in these tumours. Alternative splicing of pre-mRNAs plays an important role in the regulation of apoptosis, and the Ser-Rich Arg (SR) proteins are among the key regulators involved in both constitutive and alternative splicing events. However, less is known about their upstream activators as well as their downstream targets during apoptotic process.
In this study, we identify the splicing factor SC35, a member of this family, as a new direct transcriptional target of E2F1. Furthermore, we show that E2F1 directly interacts with SC35 and provide further evidence that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as caspases-8, -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 and SC35 proteins are up regulated and involved in the apoptotic response induced by DNA damaging agents. Taken together, these results demonstrate for the first time that E2F1 controls pre-mRNA processing events to induce apoptosis, and provide the first evidence of a functional relationship between E2F1 and SR proteins. Moreover, we show that SC35 is also implicated in the control of E2F1 proliferative functions. VEGF-A exist in most tissues as multiple isoforms, termed VEGFxxx (with pro-angiogenic properties) and VEGFxxxb (with anti-angiogenic properties) that are generated by alternative splicing of a single gene product and are deregulated in tumours. In the second part of this work we provide evidence that E2F1, but not a mutant E2F1 unable to bind DNA, down-regulates VEGF promoter activity in normoxic conditions, in a p53- independent manner. More importantly, we further provide evidence that E2F1 up regulates the expression level of anti-angiogenic VEGFxxxb isoforms, suggesting that that E2F1 selectively enhances the inclusion of VEGF-A alternative exon 8b. These findings demonstrate that E2F1 affects the angiogenic balance of VEGF isoforms in favour of anti-angiogenic splice variants. Our results suggest that the splicing factor SC35 also contributes to this splicing switch depending on the cellular models. Therefore, alterations of E2F1 and SC35 protein status in human lung tumours likely contribute to the carcinogenesis and progression of theses tumours by modifying the alternative splicing pattern of apoptotic genes, as well as by modifying the angiogenic process.
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https://tel.archives-ouvertes.fr/tel-00411680
Contributor : Galina Merdzhanova <>
Submitted on : Friday, August 28, 2009 - 3:13:02 PM
Last modification on : Thursday, January 11, 2018 - 6:20:15 AM
Long-term archiving on: : Tuesday, June 15, 2010 - 10:54:43 PM

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  • HAL Id : tel-00411680, version 1

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Galina Merdzhanova. NOUVELLES FONCTIONS DE LA PROTEINE E2F1 DANS LE CONTROLE DE L'EPISSAGE DES TRANSCRITS: IMPLICATION DANS LA CARCINOGENESE BRONCHIQUE. Biologie cellulaire. Université Joseph-Fourier - Grenoble I, 2009. Français. ⟨tel-00411680⟩

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