Transcriptional repression of the E2F-1 gene by interferon-α is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes

• Published in: Oncogene Vol. 18; no. 11; pp. 2003 - 2014
• Main Authors: FURUKAWA, Y, IWASE, S, KIKUCHI, J, NAKAMURA, M, YAMADA, H, MATSUDA, M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 18.03.1999; Nature Publishing Group
• Subjects: Binding Sites; Biological and medical sciences; Carrier Proteins; Cell Cycle Proteins; Cell Division; Cell physiology; Dephosphorylation; DNA-Binding Proteins - metabolism; Down-Regulation; E2F protein; E2F Transcription Factors; E2F1 protein; E2F1 Transcription Factor; E2F4 Transcription Factor; E2F5 Transcription Factor; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation - drug effects; Gene silencing; Humans; Interferon-alpha - pharmacology; Molecular and cellular biology; Phosphoproteins - metabolism; Phosphorylation; Promoter Regions, Genetic; Proteins; Repressors; Responses to growth factors, tumor promotors, other factors; Retinoblastoma; Retinoblastoma Protein - metabolism; Retinoblastoma-Binding Protein 1; Retinoblastoma-Like Protein p130; Transcription Factor DP1; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Up-Regulation; α-Interferon; Human; Regulation(control); Cell line; Gene; Alpha interferon; Transcription promoter; Cytokine; Retinoblastoma protein; Molecular interaction; Molecular complex; Gene expression; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1202500

E2F is a heterodimeric transcription factor composed of one of five E2F subunits (E2F-1 to E2F-5) and a DP subunit. E2F regulates the expression of several growth-promoting genes, and thus, can be a target of antiproliferative action of interferons (IFNs). In this study, we investigated the mechanisms whereby IFN-alpha suppresses transcription of the E2F-1 gene. Transfection studies revealed that E2F-1 promoter was functionally divided into two parts: upstream activation sequences (UAS) and a downstream negative-regulatory element (E2F-binding sites). When cells were proliferating, transcription of the E2F-1 gene was primarily driven by the UAS, while E2F sites were not involved in activation. IFN-alpha markedly reduced E2F-1 promoter activity, but introduction of non-binding mutation at the E2F sites completely abrogated the inhibition. Free E2F4 was found to be the predominant species bound to the E2F sites in proliferating cells. IFN-alpha induced upregulation of E2F-4 along with dephosphorylation of pRB and p130, which resulted in the formation of E2F-4/pRB and E2F-4/p130 complexes on the E2F-1 promoter. These complexes function as transcriptional repressors to inhibit E2F-1 mRNA expression. Our findings indicate that E2F-4 is a critical regulator of E2F-1, which offer an excellent paradigm for understanding functional diversity within the E2F family.