| Summary: | <i>Usp22</i> overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. <i>Usp22</i> is the catalytic subunit of the deubiquitylation module in the SAGA histone-modifying complex, which regulates gene transcription. Our previous work demonstrated that the loss of <i>Usp22</i> in mice leads to decreased expression of several components of receptor tyrosine kinase and TGFβ signaling pathways. To determine whether these pathways are upregulated when <i>Usp22</i> is overexpressed, we created a mouse model that expresses high levels of <i>Usp22</i> in all tissues. Phenotypic characterization of these mice revealed over-branching of the mammary glands in females. Transcriptomic analyses indicate the upregulation of key pathways involved in mammary gland branching in mammary epithelial cells derived from the <i>Usp22</i>-overexpressing mice, including estrogen receptor, ERK/MAPK, and TGFβ signaling. However, <i>Usp22</i> overexpression did not lead to increased tumorigenesis in any tissue. Our findings indicate that elevated levels of <i>Usp22</i> are not sufficient to induce tumors, but it may enhance signaling abnormalities associated with oncogenesis.
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