A Mouse Model to Assess STAT3 and STAT5A/B Combined Inhibition in Health and Disease Conditions

• Main Authors: Herwig P. Moll, Julian Mohrherr, Leander Blaas, Monica Musteanu, Patricia Stiedl, Beatrice Grabner, Katalin Zboray, Margit König, Dagmar Stoiber, Thomas Rülicke, Sabine Strehl, Robert Eferl, Emilio Casanova
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: Cancers
• Subjects: bacterial artificial chromosome; recombineering; Cre/loxP; gene targeting; embryonic stem cells; liver steatosis
• Online Access: https://www.mdpi.com/2072-6694/11/9/1226
• ISSN: 2072-6694

Genetically-engineered mouse models (GEMMs) lacking diseased-associated gene(s) globally or in a tissue-specific manner represent an attractive tool with which to assess the efficacy and toxicity of targeted pharmacological inhibitors. <i>Stat3</i> and <i>Stat5a/b</i> transcription factors have been implicated in several pathophysiological conditions, and pharmacological inhibition of both transcription factors has been proposed to treat certain diseases, such as malignancies. To model combined inhibition of <i>Stat3</i> and <i>Stat5a/b</i> we have developed a GEMM harboring a flox <i>Stat3</i>-<i>Stat5a/b</i> allele (<i>Stat5/3^loxP/loxP</i> mice) and generated mice lacking <i>Stat3</i> and <i>Stat5a/b</i> in hepatocytes (<i>Stat5/3^&#916;hep</i>^{/<i>&#916;hep</i>}). <i>Stat5/3^{&#916;hep/&#916;hep}</i> mice exhibited a marked reduction of STAT3, STAT5A and STAT5B proteins in the liver and developed steatosis, a phenotype that resembles mice lacking <i>Stat5a/b</i> in hepatocytes. In addition, embryonic deletion of <i>Stat3</i> and <i>Stat5a/b</i> (<i>Stat5/3^&#916;</i>^{/<i>&#916;</i>} mice) resulted in lethality, similar to <i>Stat3^&#916;</i>^{/<i>&#916;</i>} mice. This data illustrates that <i>Stat5/3^loxP/loxP</i> mice are functional and can be used as a valuable tool to model the combined inhibition of <i>Stat3</i> and <i>Stat5a/b</i> in tumorigenesis and other diseases.