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Baran-Marszak, F.* ; Feuillard, J.* ; Najjar, I.* ; Le Clorennec, Ch.* ; Bechét, J.-P.* ; Dusanter-Fourt, I.* ; Bornkamm, G.W. ; Raphaël, M.* ; Fagard, R.*

Differential roles of STAT1alpha and STAT1beta in fludarabine-induced cell cycle arrest and apoptosis in human B cells.

Blood 104, 2475-2483 (2004)
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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, STAT1α, was specifically inhibited by the overexpression of STAT1β, the STAT1α truncated inhibitory isoform. An episomal vector with a tetracycline-inducible bidirectional promoter was created to induce the expression of 2 proteins, STAT1β and enhanced green fluorescence protein (EGFP). The same vector was used to overexpress STAT1α as a control. Expression of STAT1β inhibited the phosphorylation, the DNA-binding activity, and the transcriptional activity of STAT1α, as well as the expression of STAT1α target genes such as p21WAF1/CIP1, TAP1, IRF1, and PKR. Inhibiting STAT1α by STAT1β increased the growth rate of transfected cells and their resistance to fludarabine-induced apoptosis and cell cycle arrest. Overexpressing STAT1β reversed the negative regulation of Mdm2 expression observed after treatment with interferon-gamma (IFN-γ), which activates STAT1, or with fludarabine. Nuclear translocation of p53 after fludarabine treatment was decreased when STAT1β was overexpressed, and it was increased when STAT1α was induced. Oligonucleotide pull-down experiments showed a physical STAT1/p53 interaction. Our results show that imbalance between the antiproliferative/proapoptotic isoform STAT1α and the proliferative isoform STAT1β is likely to play a crucial role in the regulation of proliferation and apoptosis and that STAT1α may regulate p53 activity and sensitize B cells to fludarabine-induced apoptosis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2004
HGF-Berichtsjahr 0
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Quellenangaben Band: 104, Heft: 8, Seiten: 2475-2483 Artikelnummer: , Supplement: ,
Verlag American Society of Hematology
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501400-006
DOI 10.1182/blood-2003-10-3508
Erfassungsdatum 2004-10-04
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