Unr, a cytoplasmic RNA-binding protein with cold-shock domains, is involved in control of apoptosis in ES and HuH7 cells.
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 approximately 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 Gadd45gamma, 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 gamma-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.
Dormoy-Raclet
V
V
INSERM, E362, Bordeaux, France.
Markovits
J
J
Malato
Y
Y
Huet
S
S
Lagarde
P
P
Montaudon
D
D
Jacquemin-Sablon
A
A
Jacquemin-Sablon
H
H
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division; D049109:Cell Proliferation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D016195:G2 Phase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D039102:Poly(A)-Binding Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011839:Radiation, Ionizing; D013234:Stem Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097642:GADD45 Proteins
D002352:Carrier Proteins; D053148:Caspase 3; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C079950:CSDE1 protein, human; C485654:GADD45G protein, human; D000097642:GADD45 Proteins; C121373:Gadd45g protein, mouse; C489441:UNR protein, mouse