1. ¹INSERM, E362, Bordeaux, France
2. ²Université Victor Segalen Bordeaux 2, Bordeaux, France
3. ³CNRS, FRE 2618, Institut Bergonié, Bordeaux, France

Correspondence: Dr H Jacquemin-Sablon, GREF, INSERM E362, Université Bordeaux 2, 146 rue Léo Saignat, Bordeaux cedex 33076, France. E-mail: helene.jacquemin-sablon@gref.u-bordeaux2.fr

⁴These authors contributed equally to this work.

Received 4 February 2005; Revised 28 July 2006; Accepted 8 September 2006; Published online 6 November 2006.

Abstract

Unr (upstream of N-ras) is a cytoplasmic RNA-binding protein involved in the regulation of messenger RNA stability and internal initiation of translation. We have used Unr-deficient murine embryonic stem (ES) cells to analyse Unr role in cell proliferation and response to stress. Disruption of both unr gene copies had no effect on ES cell proliferation. However, after ionizing radiation (IR), clonogenic survival of unr^-/- ES cells was 3-fold enhanced as compared to unr^+/+ cells. We further determined that IR-induced apoptosis was decreased in unr^-/- ES cells, and that reintroduction of the unr gene in unr^-/- cells restored normal IR-induced apoptosis. Three pro-apoptotic genes, p53, caspase-3 and Gadd45, were downregulated in unr^-/- ES cells, indicating that Unr, as other cytoplasmic RNA-binding proteins, regulates a complex genetic program, promoting cell death after IR. In contrast, in the human hepatoma cell line HuH7, Unr knockdown using unr-specific small interfering RNAs induced apoptosis, both in untreated and -irradiated cells. Thus, our results establish that Unr acts as a positive or negative regulator of cell death, depending on the cell type. Manipulating the level of Unr may constitute a specific approach to sensitize cancer cells to anticancer treatments.