title: The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7.
abstract: Down syndrome is the most common genetic disorder and is characterized by three copies of chromosome 21. Regulator of calcineurin 1 (RCAN1) is located close to the Down syndrome critical region (distal part of chromosome 21), and its product functions as an endogenous inhibitor of calcineurin signaling. RCAN1 protein stability is regulated by several inflammatory signaling factors, though the underlying mechanisms remain incompletely understood. Here, we report that RCAN1 interacts with the inflammation-linked transcription factor, signal transducer and activator of transcription 2 (STAT2) in mammalian cells. STAT2 overexpression decreased levels of RCAN1 protein. Decreases in RCAN1 were blocked by a proteasome inhibitor, indicating that STAT2 regulates RCAN1 degradation via the ubiquitin-proteasome system. Co-immunoprecipitation/immunoblot analyses showed that STAT2 enhanced RCAN1 ubiquitination through the ubiquitin E3 ligase FBW7. This pathway appeared to be physiologically relevant, as treatment of cells with interferon-α reduced RCAN1 levels through the activation of STAT2 and FBW7. Together, these results suggest that STAT2 influences diverse cellular processes linked to RCAN1 by negatively affecting RCAN1 protein stability.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Jee Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Hye Seon
authors.initials: HS
authors.lastname: Kang
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Lee
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.forename: Joo Heon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Su Ryeon
authors.initials: SR
authors.lastname: Seo
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D018836:Inflammation Mediators; D016898:Interferon-alpha; D009124:Muscle Proteins; C100360:RCAN2 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex