Negative regulation of the IFN/STAT signaling pathway by the Trim24 tumor suppressor protein through Rara inhibition
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ABSTRACT: Recent genetic studies in mice have established a key role for the nuclear receptor coregulator Trim24 in liver tumor suppression and provided evidence that Trim24 suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor alpha (Rara)-dependent transcription and cell proliferation. However, it is unknown which downstream targets of Rara regulated by Trim24 are critical for tumorigenesis. We report here that loss of Trim24 results in the overexpression of interferon (IFN)/STAT pathway genes in the liver, a process that occurs early in tumorigenesis and is more pronounced in tumors, despite the enhanced expression, late in the disease, of negative regulators such as Usp18, Socs1 and Socs2. Remarkably, Rara haplodeficiency, which was previously shown to suppress tumor development in Trim24-/- mice, also suppresses overexpression of the IFN/STAT pathway, thus providing evidence for a cross-pathway control that may be relevant to the transformation process. Biochemical studies revealed that Trim24 binds to the retinoic acid (RA)-responsive element in the Stat1 promoter in a RA-dependent manner and represses RA-induced transcription from this promoter. Together, these results identify Trim24 as a novel regulator of the IFN/STAT pathway and indicate that Trim24-mediated repression of the IFN/STAT signaling through Rara inhibition may play a critical role in preventing liver cancer.
ORGANISM(S): Mus musculus
PROVIDER: GSE19675 | GEO | 2011/08/02
SECONDARY ACCESSION(S): PRJNA122499
REPOSITORIES: GEO
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