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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2475-2483.
Prepublished online as a Blood First Edition Paper on June 24, 2004; DOI 10.1182/blood-2003-10-3508.
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Submitted October 15, 2003
Accepted April 21, 2004
Differential roles of STAT1 and STAT1 in Fludarabine-induced cell cycle arrest and apoptosis in human B-cells
Fanny Baran-Marszak, Jean Feuillard*, Imen Najjar, Christophe Le Clorennec, Jean-Marie Bechet, Isabelle Dusanter-Fourt, Georg W Bornkamm, Martine Raphael, and Remi Fagard
UPRES EA 3406 Agents Transmissibles et Hotes, Signalisation Cellulaire et Oncogenese, Universite Paris 13, Bobigny, France; INSERM E109 et Service d'Hematologie Biologique, Universite Paris 11, Kremlin-Bicetre, France
Laboratoire d'Hematologie et UMR CNRS 6101, Universite de Limoges, Limoges, France
UPRES EA 3406 Agents Transmissibles et Hotes, Signalisation Cellulaire et Oncogenese, Universite Paris 13, Bobigny, France
UMR 6551, Universite de Caen, Caen, France
Unite INSERM ICGM, Hopital Cochin Port Royal, Paris, France
Institute of Clinical Molecular Biology and Tumor Genetics, GSF, Munich, Germany
INSERM E109 et Service d'Hematologie Biologique, Universite Paris 11, Kremlin-Bicetre, France
* Corresponding author; email: jean.feuillard{at}chu-limoges.fr.
STAT1, a transcription factor known to participate in antiviral responses, act as a tumor suppressor inhibiting cell growth and promoting apoptosis. To study the role of STAT1 in DNA damage induced apoptosis in B lymphocytes, its active form STAT1[[alpha was specifically inhibited by overexpression of STAT1 , the STAT1 truncated inhibitory isoform. An episomal vector with a tetracycline-inducible bi-directional promoter was created to induce the expression of two proteins, STAT1 and the Green Fluorescent Protein (EGFP). The same vector was used to over-express STAT1 as a control. Expression of STAT1 inhibited the phosphorylation, the DNA-binding activity and the transcriptional activity of STAT1, as well as the expression of STAT1 target genes such as p21WAF1/CIP1, TAP1, IRF1 and PKR. Inhibition of STAT1 by STAT1 increased the growth rate of transfected cells and their resistance to Fludarabine-induced apoptosis and cell cycle arrest. Overexpression of STAT1 reversed the negative regulation of Mdm2 expression observed after treatment with IFN , which activates STAT1, or with Fludarabine. Nuclear translocation of p53 following Fludarabine treatment was decreased when STAT1 was overexpressed and was increased when STAT1 was induced. Oligonucleotide pull-down experiments showed a physical STAT1/p53 interaction. Our results show that imbalance between the antiproliferative/proapoptotic isoform STAT1 and the proliferative isoform STAT1 is likely to play a crucial role in the regulation of proliferation and apoptosis and that STAT1 may regulate p53 activity and sensitize B-cells to Fludarabine induced apoptosis.
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