Oncotarget

Research Papers:

Expression of the p66Shc protein adaptor is regulated by the activator of transcription STAT4 in normal and chronic lymphocytic leukemia B cells

Francesca Cattaneo, Laura Patrussi, Nagaja Capitani, Federica Frezzato, Mario Milco D’Elios, Livio Trentin, Gianpietro Semenzato and Cosima T. Baldari _

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Oncotarget. 2016; 7:57086-57098. https://doi.org/10.18632/oncotarget.10977

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Abstract

Francesca Cattaneo1, Laura Patrussi1, Nagaja Capitani1,2, Federica Frezzato3, Mario Milco D’Elios2, Livio Trentin3, Gianpietro Semenzato3, Cosima T. Baldari1

1Department of Life Sciences, University of Siena, Siena, Italy

2Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy

3Department of Medicine, University of Padua, Padova, Italy

Correspondence to:

Cosima T. Baldari, email: cosima.baldari@unisi.it

Francesca Cattaneo, email: francesca.cattaneo@unisi.it

Keywords: transcriptional regulation, p66Shc, STAT4, lisofylline, CLL

Received: April 15, 2016    Accepted: July 19, 2016    Published: August 01, 2016

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.


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