SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation.
Sex-determining region Y-box (SOX) 6 negatively regulates glucose-stimulated insulin secretion from beta-cells and is a down-regulated transcription factor in the pancreatic islet cells of hyperinsulinemic obese mice. To determine the contribution of SOX6 to insulin resistance, we analyzed the effects of SOX6 on cell proliferation. Small interfering RNA-mediated attenuation of SOX6 expression stimulated the proliferation of insulinoma INS-1E and NIH-3T3 cells, whereas retroviral overexpression resulted in inhibition of cell growth. Quantitative real time-PCR analysis revealed that the levels of cyclin D1 transcripts were markedly decreased by SOX6 overexpression. Luciferase-reporter assay with beta-catenin showed that SOX6 suppresses cyclin D1 promoter activities. In vitro binding experiments showed that the LZ/Q domain of SOX6 physically interacts with armadillo repeats 1-4 of beta-catenin. Furthermore, chromatin immunoprecipitation assay revealed that increased SOX6 expression significantly reduced the levels of acetylated histones H3 and H4 at the cyclin D1 promoter. By using a histone deacetylase (HDAC) inhibitor and co-immunoprecipitation analysis, we showed that SOX6 suppressed cyclin D1 activities by interacting withbeta-catenin and HDAC1. The data presented suggest that SOX6 may be an important factor in obesity-related insulin resistance.
Iguchi
Haruhisa
H
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
Urashima
Yasuyo
Y
Inagaki
Yosuke
Y
Ikeda
Yukio
Y
Okamura
Masashi
M
Tanaka
Toshiya
T
Uchida
Aoi
A
Yamamoto
Tokuo T
TT
Kodama
Tatsuhiko
T
Sakai
Juro
J
D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D006609:High Mobility Group Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D007340:Insulinoma; D007668:Kidney / Q000166:cytology; D016350:Leucine Zippers / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010190:Pancreatic Neoplasms; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D055755:SOXD Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D051176:beta Catenin / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D006657:Histones; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases