Identification of target genes of the transcription factor HNF1beta and HNF1alpha in a human embryonic kidney cell line.
Hepatocyte nuclear factor 1beta (HNF1beta, TCF2) is a tissue-specific transcription factor whose mutation in humans leads to renal cysts, genital malformations, pancreas atrophy and maturity onset diabetes of the young (MODY5). Furthermore, HNF1beta overexpression has been observed in clear cell cancer of the ovary. To identify potential HNF1beta target genes whose activity may be deregulated in human patients, we established a human embryonic kidney cell line (HEK293) expressing HNF1beta conditionally. Using Flp recombinase, we introduced wild type or mutated HNF1beta at a defined chromosomal position allowing a most reproducible induction of the HNF1beta derivatives upon tetracycline addition. By oligonucleotide microarrays we identified 25 HNF1beta-regulated genes. By an identical approach, we identified that the related transcription factor HNF1alpha (TCF1) affects only nine genes in HEK293 cells and thus is a less efficient factor in these kidney cells. The HNF1beta target genes dipeptidyl peptidase 4 (DPP4), angiotensin converting enzyme 2 (ACE2) and osteopontin (SPP1) are most likely direct target genes, as they contain functional HNF1 binding sites in their promoter region. Since nine of the potential HNF1beta target genes are deregulated in clear cell carcinoma of the ovary, we propose that HNF1beta overexpression in the ovarian cancer participates in the altered expression pattern.
Senkel
Sabine
S
Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, D-45122 Essen, Germany.
Lucas
Belén
B
Klein-Hitpass
Ludger
L
Ryffel
Gerhart U
GU
D000085962:Angiotensin-Converting Enzyme 2; D001483:Base Sequence; D002268:Carboxypeptidases / Q000378:metabolism; D004254:DNA Nucleotidyltransferases / Q000235:genetics; D005786:Gene Expression Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism* / Q000502:physiology; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D053495:Osteopontin; D007703:Peptidyl-Dipeptidase A; D011401:Promoter Regions, Genetic; D012795:Sialoglycoproteins / Q000378:metabolism; D013752:Tetracycline / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D014157:Transcription Factors; D053495:Osteopontin; D051539:Hepatocyte Nuclear Factor 1-beta; D004254:DNA Nucleotidyltransferases; C045119:FLP recombinase; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D013752:Tetracycline