HNF1alpha upregulates the human AE2 anion exchanger gene (SLC4A2) from an alternate promoter.
The human AE2 gene (SLC4A2) is transcribed in a widespread fashion from the upstream promoter, the resultant full-length transcript AE2a being encountered in most tissues. Moreover, alternate promoter sequences within intron 2 may drive tissue-restricted expression of variants AE2b(1) and AE2b(2), mainly in liver and kidney. AE2b(2) proximal promoter sequences are highly active in transfected liver-derived HepG2 cells and contain an HNF1 motif. Mutation-disruption of this motif dramatically decreased alternate promoter activity in HepG2 cells but not in prostate-derived PC-3 cells. Electromobility shift and supershift assays indicated that HNF1alpha from HepG2 nuclear extracts binds the HNF1 sequence. Transactivation studies in PC-3 cells showed enhanced activity of the wild-type construct upon cotransfection with an HNF1alpha expression plasmid, while activity of the HNF1-mutated construct remained unaffected. Since liver AE2 is putatively involved in the biliary secretion of bicarbonate, HNF1alpha may have a role in increasing bicarbonate secretion in response to certain stimuli.
Laboratory of Molecular Genetics, Division of Hepatology and Gene Therapy, CIMA, University Clinic and Medical School, University of Navarra, E-31008 Pamplona, Spain.
Raquel
R
Malumbres
Jon
J
Lecanda
Saida
S
Melero
Pawel
P
Ciesielczyk
Jesús
J
Prieto
Juan F
JF
Medina
D020816:Amino Acid Motifs; D027321:Anion Transport Proteins; D017920:Antiporters; D045744:Cell Line, Tumor; D027963:Chloride-Bicarbonate Antiporters; D004268:DNA-Binding Proteins; D018197:Hepatoblastoma / Q000235:genetics* / Q000378:metabolism*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D064606:SLC4A Proteins; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D027321:Anion Transport Proteins; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D008565:Membrane Proteins; D009687:Nuclear Proteins; D064606:SLC4A Proteins; C579496:SLC4A2 protein, human; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta