title: Expression of the p66Shc protein adaptor is regulated by the activator of transcription STAT4 in normal and chronic lymphocytic leukemia B cells.
abstract: p66Shc attenuates mitogenic, prosurvival and chemotactic signaling and promotes apoptosis in lymphocytes. Consistently, p66Shc deficiency contributes to the survival and trafficking abnormalities of chronic lymphocytic leukemia (CLL) B cells. The mechanism of p66shc silencing in CLL B cells is methylation-independent, at variance with other cancer cell types. Here we identify STAT4 as a novel transcriptional regulator of p66Shc in B cells. Chromatin immunoprecipitation and reporter gene assays showed that STAT4 binds to and activates the p66shc promoter. Silencing or overexpression of STAT4 resulted in a co-modulation of p66Shc. IL-12-dependent STAT4 activation caused a coordinate increase in STAT4 and p66Shc expression, which correlated with enhanced B cell apoptosis. Treatment with the STAT4 inhibitor lisofylline reverted partly this effect, suggesting that STAT4 phosphorylation is not essential for but enhances p66shc transcription. Additionally, we demonstrate that CLL B lymphocytes have a STAT4 expression defect which partly accounts for their p66Shc deficiency, as supported by reconstitution experiments. Finally, we show that p66Shc participates in a positive feedback loop to promote STAT4 expression. These results provide new insights into the mechanism of p66Shc expression in B cells and its defect in CLL, identifying the STAT4/IL-12 pathway as a potential therapeutic target in this neoplasia.
authors: Department of Life Sciences, University of Siena, Siena, Italy.
authors: Francesca
authors: F
authors: Cattaneo
authors: Department of Life Sciences, University of Siena, Siena, Italy.
authors: Laura
authors: L
authors: Patrussi
authors: Department of Life Sciences, University of Siena, Siena, Italy.|Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy.
authors: Nagaja
authors: N
authors: Capitani
authors: Department of Medicine, University of Padua, Padova, Italy.
authors: Federica
authors: F
authors: Frezzato
authors: Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy.
authors: Mario Milco
authors: MM
authors: D'Elios
authors: Department of Medicine, University of Padua, Padova, Italy.
authors: Livio
authors: L
authors: Trentin
authors: Department of Medicine, University of Padua, Padova, Italy.
authors: Gianpietro
authors: G
authors: Semenzato
authors: Department of Life Sciences, University of Siena, Siena, Italy.
authors: Cosima T
authors: CT
authors: Baldari
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000737:chemistry; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: C528024:SHC1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018664:Interleukin-12; C025189:lisofylline; D010431:Pentoxifylline
keywords: CLL; STAT4; lisofylline; p66Shc; transcriptional regulation