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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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NEOPLASIA
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 Béchet,
Isabelle Dusanter-Fourt,
Georg W. Bornkamm,
Martine Raphaël, and
Remi Fagard
From the Equipe d'Accueil 3406 Université Paris 13, Service de Biochimie, Hôpital Avicenne, France; Unité Mixte de Recherche (UMR) Centre National de la Recherche Scientifique (CNRS) 6101 and Laboratoire d'Hématologie, Centre Hospitalier Universitaire (CHU) Dupuytren and Faculté de Médecine, Université de Limoges, France; Institut National de la Santé et de la Recherche Médicale (INSERM) E109, Université Paris 11, Kremlin-Bicêtre, France; UMR 6551, Université de Caen, France; Unité INSERM Institut Cochin de Génétique Moléculaire (ICGM) Cochin Port-Royal, France; and Forschungszentrum für Umwelt und Gesundheit (GSF)–Institute of Clinical Molecular Biology and Tumor Genetics, Munich, Germany.
Signal transducer and activator of transcription 1 (STAT1), a transcription factor known to participate in antiviral responses, acts 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 , was specifically inhibited by the overexpression of STAT1 , the STAT1 truncated inhibitory isoform. An episomal vector with a tetracycline-inducible bidirectional promoter was created to induce the expression of 2 proteins, STAT1 and enhanced green fluorescence protein (EGFP). The same vector was used to overexpress 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. Inhibiting STAT1 by STAT1 increased the growth rate of transfected cells and their resistance to fludarabine-induced apoptosis and cell cycle arrest. Overexpressing STAT1 reversed the negative regulation of Mdm2 expression observed after treatment with interferon-gamma (IFN- ), which activates STAT1, or with fludarabine. Nuclear translocation of p53 after fludarabine treatment was decreased when STAT1 was overexpressed, and it 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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