期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 38, 页码 33369-33379出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.225680
关键词
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资金
- CNRS
- INSERM
- Agence Nationale de la Recherche [ANR06-BLAN-0377]
- Association pour la Recherche contre le Cancer (ARC)
- Ligue Nationale Contre le Cancer
- Institut National du Cancer (INCa)
- ARTOn
- Ministere de la Recherche et des Technologies
- ARC
- INCa
- ARI (Agence Regionale de l'Innovation)
Recent genetic studies in mice have established that the nuclear receptor coregulator Trim24/Tif1 alpha suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor alpha (Rara)-dependent transcription and cell proliferation. However, Rara targets regulated by Trim24 remain unknown. We report that the loss of Trim24 resulted in interferon (IFN)/STAT pathway overactivation soon after birth (week 5). Despite a transient attenuation of this pathway by the induction of several IFN/STAT pathway repressors later in the disease, this phenomenon became more pronounced in tumors. Remarkably, Rara haplo-deficiency, which suppresses tumorigenesis in Trim24(-/-) mice, prevented IFN/STAT overactivation. Moreover, together with Rara, Trim24 bound to the retinoic acid-responsive element of the Stat1 promoter and repressed its retinoic acid-induced transcription. Altogether, these results identify Trim24 as a novel negative regulator of the IFN/STAT pathway and suggest that this repression through Rara inhibition may prevent liver cancer.
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