Nuclear Organisation and Oncogenesis - INSERM U.993  


  HEADDr DEJEAN Anne / adejean@pasteur.fr
  MEMBERSDr BISCHOF Oliver / Dr PINEAU Pascal / Dr. SEELER Jacob / Pr TIOLLAIS Pierre Dr BENHAMED Moussa / Dr DEMARQUE Maud / Dr FRITAH Sabrina / Dr SAHIN Umut NEYRET-KAHN Hélène / DECQUE Adrien / MARCHIO Agnès / ANDRIEUX Alexandra / DA Louise-Marie / GEORGES Monique / LEGUEULT Catherine / QUEROL Chantal


  Annual Report

The work in our lab is dedicated to the study of the molecular and cellular mechanisms involved in the development of human cancers with a particular emphasis on the role of certain post-translational modifications. Apart from the potential clinical applications, the study of the events underlying oncogenic transformation is also aimed at revealing novel fundamental biological processes in normal cells. Our work combines fundamental projects, based on experimental systems, as well as more clinically-oriented projects devoted to the study of human liver cancer.

Genetics and epigenetics of primary liver cancer

A first, 'global' approach seeks to establish a general profile of genetic, epigenetic or post-transcriptional alterations associated with hepatocellular carcinoma (HCC). To this aim : (i) mutational and functional analyses have been conducted for candidate tumor suppressor genes. (ii) we studied general and specific profiles of chromatin modifications, both at the histone and DNA levels, (iii) we initiated a comprehensive characterization of the miRNAs differentially expressed in HCC. We identified a signature of 12 miRNAs specifically associated with HCC progression, the role of which is subject of further study.

Role of the SUMO pathway in healthy and diseased cells

A second, more 'mechanistic' approach, centers on the role of the SUMO pathway in both development and disease. The first axis aimed at characterizing novel components associated with this pathway. We identified PARP1 as a new SUMO target and describe a novel mechanism of regulation of PARP1 transcriptional activity through a sumoylation-coupled ubiquitination pathway. In parallel, we identified the SUMO E3 ligase PIASy as an important co-regulator of FIP200 function and provided the first evidence for the existence of a close, spatially controlled, interplay between PIASy and FIP200 in the regulation of TSC/mTOR signaling.

The second research axis was devoted to study the role of sumoylation in vivo using animal models deficient/attenuated for sumoylation. We have generated a series of mice in which expression of the SUMO E2 enzyme Ubc9 is reduced in a conditional and graded fashion from normal to zero by the use of various combinations of wild-type, hypomorphic and knock-out alleles (Ubc9+/+ › Ubc9+/H › Ubc9+/- › Ubc9-/H › Ubc9-/-). Acute loss of Ubc9 at the adult stage revealed a key role for sumoylation in stem cell maintenance and in controlling homeostasis and mechanical stability of the intestinal epithelium.

Lack of sumoylation leads to rapid loss of stem cells

The elaboration of cellular and animal models deficient for sumoylation should now provide valuable tools for the elucidation of the general roles of this pathway in normal and disease-related fundamental processes.

Transcriptional gene silencing in cellular senescence

The last research axis aims at studying the formation of senescence-associated inactive chromatin. We provide evidence that argonaute protein Ago2 and specific microRNAs play a decisive role in the repression of Rb/E2F target genes in senescence, a process that we refer to as senescence-associated transcriptional gene silencing (SA-TGS) and identify cellular senescence as the first endogenous signal of miR-AGO-mediated TGS in human cells.

Keywords: Oncogenesis, Post-translational modifications, Epigenetics, Chromatin, Sumoylation, Cellular senescence, Liver cancer

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Lack of sumoylation leads to rapid loss of stem cells



  Publications

Pineau, P., Volinia, S., McJunkin, K, Marchio, A., Mazzaferro, V., Terris, B., Lowe, S., Croce, C.and Dejean A. miR-221 overexpression contributes to liver carcinogenesis. PNAS, 2010, 107, 264-269.

Martin, N*., Schwamborn, K*., Urlaub, H., Gan, B., Guan, J.L. and Dejean, A. (2008) (* co-first authors) Spatial interplay between PIASy and FIP200 in the regulation of signal transduction and transcriptional activity. Mol Cell Biol., 28, 2771-2781.

Martin, N., Schwamborn, K., Schreiber, V., Werner, A., Guillier, C., Zhang, X-D., Bischof, O., Seeler, J., and Dejean, A. PARP1 transcriptional activity is regulated by sumoylation upon heat shock. EMBO J, 2009, 18, 3534-48.

Kumar, P.,Bischof, O.,Kumar Purbey, P., Notani, D., Urlaub, H., Dejean, A., and Galande, S. Functional Interaction between PML and SATB1 Regulates Chromatin Loop Architecture and Transcription of the MHC class I Locus. Nat Cell Biol,2007, 9, 45-56.





Activity Reports 2010 - Institut Pasteur
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