RGD Reference Report - SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. - Rat Genome Database

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SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice.

Authors: Iguchi, H  Ikeda, Y  Okamura, M  Tanaka, T  Urashima, Y  Ohguchi, H  Takayasu, S  Kojima, N  Iwasaki, S  Ohashi, R  Jiang, S  Hasegawa, G  Ioka, RX  Magoori, K  Sumi, K  Maejima, T  Uchida, A  Naito, M  Osborne, TF  Yanagisawa, M  Yamamoto, TT  Kodama, T  Sakai, J 
Citation: Iguchi H, etal., J Biol Chem. 2005 Nov 11;280(45):37669-80. Epub 2005 Sep 7.
RGD ID: 1581307
Pubmed: PMID:16148004   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M505392200   (Journal Full-text)

In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing beta-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca(2+) mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein/protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of histones H3 and H4 in chromatin from the promoter for the insulin II gene, suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in beta-cells may contribute to the beta-cell adaptation in obesity-related insulin resistance.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Insulin Resistance  ISOSox6 (Mus musculus)1581307; 1581307 RGD 
Insulin Resistance  IDA 1581307 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Sox6  (SRY-box transcription factor 6)

Genes (Mus musculus)
Sox6  (SRY (sex determining region Y)-box 6)

Genes (Homo sapiens)
SOX6  (SRY-box transcription factor 6)


Additional Information