RGD Reference Report - The role of HNF1alpha, HNF3gamma, and cyclic AMP in glucose-6-phosphatase gene activation. - Rat Genome Database

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The role of HNF1alpha, HNF3gamma, and cyclic AMP in glucose-6-phosphatase gene activation.

Authors: Lin, B  Morris, DW  Chou, JY 
Citation: Lin B, etal., Biochemistry. 1997 Nov 18;36(46):14096-106.
RGD ID: 8553889
Pubmed: PMID:9369482   (View Abstract at PubMed)
DOI: DOI:10.1021/bi9703249   (Journal Full-text)

The gene for glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, is expressed in a tissue-specific manner in the liver and kidney. To understand the molecular mechanisms regulating liver-specific expression of the G6Pase gene, we characterized G6Pase promoter activity by transient expression assays. The G6Pase promoter is active in HepG2 hepatoma cells, but inactive in JEG3 choriocarcinoma or 3T3 cells. DNA elements essential for optimal and liver-specific expression of the G6Pase gene were contained within nucleotides -234 to +3. Deletion analysis revealed that the G6Pase promoter contained three activation elements (AEs) at nucleotides -234 to -212 (AE-I), -146 to -125 (AE-II), and -124 to -71 (AE-III). AE-I contains binding sites for hepatocyte nuclear factors (HNF) 1 and 4. Electromobility shift and cotransfection assays demonstrated that HNF1alpha, but not HNF4, bound to its cognate site and transactivated G6Pase gene expression. The G6Pase promoter contained five HNF3 motifs, 1 (-180/-174), 2 (-139/-133), 3 (-91/-85), 4 (-81/-75), and 5 (-72/-66), and all five sites bound HNF3gamma with high affinity. Transient expression and cotransfection assays showed that HNF3 site 1 is not required for basal promoter activity, but is essential for HNF3gamma-activated transcription from the G6Pase promoter. We further showed that HNF3 sites 3, 4, and 5 were essential for basal G6Pase promoter activity and transactivation by HNF3gamma. AE-II contains, in addition to a HNF3 motif, a cAMP-response element (CRE) and a C/EBP half-site. The G6Pase(-146/-116) DNA containing AE-II formed multiple protein-DNA complexes with HepG2 nuclear extracts, including HNF3gamma, CRE-binding protein (CREB), C/EBPalpha, and C/EBPbeta. We showed that AE-II mediated transcription activation of the G6Pase gene by cAMP.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Foxa3Ratintracellular glucose homeostasis involved_inTAS PMID:9369482UniProt 
Foxa3Ratpositive regulation of transcription by RNA polymerase II involved_inIDA PMID:9369482UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Foxa3  (forkhead box A3)


Additional Information