Abstract
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. Stat3 and Stat5a/b 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 Stat3 and Stat5a/b we have developed a GEMM harboring a flox Stat3-Stat5a/b allele (Stat5/3loxP/loxP mice) and generated mice lacking Stat3 and Stat5a/b in hepatocytes (Stat5/3Δhep/Δhep). Stat5/3Δhep/Δhep mice exhibited a marked reduction of STAT3, STAT5A and STAT5B proteins in the liver and developed steatosis, a phenotype that resembles mice lacking Stat5a/b in hepatocytes. In addition, embryonic deletion of Stat3 and Stat5a/b (Stat5/3Δ/Δ mice) resulted in lethality, similar to Stat3Δ/Δ mice. This data illustrates that Stat5/3loxP/loxP mice are functional and can be used as a valuable tool to model the combined inhibition of Stat3 and Stat5a/b in tumorigenesis and other diseases.
Highlights
Genetically-engineered mouse models (GEMMs) lacking gene(s) of interest in the whole animal or in a tissue-specific manner offer a unique opportunity to model the effects of pharmacological inhibitors, as well as to assess toxicity in models of health and disease [1]
In a second recombination step, a FRT-Hygromycin-FRT-loxP cassette was introduced within the first intron of the Stat3 gene between exons 1 and 2
Stat3 exon 2 contains the ATG translation initiation codon; the flox strategy predicts the absence of a STAT3 truncated protein
Summary
Genetically-engineered mouse models (GEMMs) lacking gene(s) of interest in the whole animal or in a tissue-specific manner offer a unique opportunity to model the effects of pharmacological inhibitors, as well as to assess toxicity in models of health and disease [1]. The over-activation of STAT3 and STAT5A/B has been reported in human hematopoietic and solid malignancies, suggesting that these transcription factors behave as oncogenic drivers in those tumors [6,7]. These observations have been complemented with functional studies using GEMMs harboring flox alleles for Stat3 [8,9,10,11,12,13] and Stat5a/b [14] genes
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