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 FRITAH Sabrina / Dr SAHIN Umut / Dr BENHAMED Moussa / Dr DEMARQUE Maud NEYRET-KAHN Hélène / 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 initiated a comprehensive characterization of the miRNAs differentially expressed in HCC and unravelled an important role for miR-221 in HCC progression. Expression of miR-221 enhances proliferation of liver tumor cells in vitro and accelerates liver tumorigenesis in mice. We identified DDIT4, a modulator of mTOR pathway, as a bona fide target of miR-221. The overall contribution of the PTEN/mTOR pathway in liver carcinogenesis is now the 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 global role of sumoylation in vivo using animal models deficient/attenuated for sumoylation. To this aim, we have generated a series of mice in which

expression of 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 ubiquitous ablation of Ubc9 at the adult stage revealed a essential role for sumoylation in intestinal homeostasis. Decrease in sumoylation leads to the depletion of intestinal proliferative compartment but also define an unexpected role for this modification in maintaining the stem cell compartment and controlling positioning and differentiation along both the secretory and absorptive lineages. These data attest to the importance of this pathway for the architecture and function of the intestinal epithelium.

Finally, we investigated the role of non coding small RNAs in chromatin dynamics upon senescence and provide evidence for an involvement of small RNAs originating from DNA repeats in the establishment of the heterochromatin foci associated with senescence.

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

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Ubc9 is essential for the maintenance of stem cells in intestinal crypts



  Publications

Bischof, O.*, Schwamborn, K.*, Martin, N.,Werner, A., Sustmann, C., Grosschedl, R. and Dejean, A. (*co-first authors) (2006) The E3 SUMO ligase PIASy is a novel regulator of cellular senescence and apoptosis. Mol Cell. 22, 783-94.

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

Martin, N., Schwamborn, K., Urlaub, H., Gan, B., Guan, J.L. and Dejean, A. (2008) 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*. (*co-corresponding authors) (2009) PARP1 transcriptional activity is regulated by sumoylation upon heat shock. EMBO J, 28, 3534-3548.

Pineau, P., Volinia, S., McJunkin, K,Marchio, A., Mazzaferro, V., Terris, B., Lowe, S., Croce, C. and Dejean A. (2010) miR-22/222 contributes to liver carcinogenesis. Proc. Natl. Acad. Sci. USA,107, 264-269.





Activity Reports 2009 - Institut Pasteur
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