Coordinate regulation of 11 beta-HSD and Ke 6 genes in cpk mouse: implications for steroid metabolic defect in PKD.
Polycystic kidney disease (PKD) is characterized by multiple renal cysts, which ultimately result in renal failure. We have reported the identification of a new gene, Ke 6, within the major histocompatibility complex, which is downregulated in two different mouse models of heritable PKD (N. Aziz, M. Maxwell, B. St.-Jacques, and B.M. Brenner. Mol. Cell. Biol. 13: 1847-1853, 1993). The Ke 6 gene gives rise to two transcripts, Ke 6a and Ke 6b. Ke 6a protein has significant homology to several mammalian and bacterial steroid dehydrogenases. The homology of Ke 6a protein to specific functional domains of the human and rat 11 beta-hydroxysteroid dehydrogenase enzyme (11 beta-HSD), which inactivates glucocorticoids, is substantial. We report here that the Ke 6 gene and the 11 beta-HSD gene are regulated in the same aberrant pattern in the cpk mouse. The strong evidence for a critical role of steroids in cystogenesis leads us to propose that a possible elevation of intrahepatic and intrarenal steroid levels occurs in the cpk mouse as a result of repression of steroid metabolic enzymes, which ultimately leads to development of cysts.
Aziz
N
N
Department of Medicine, Children's Hospital, Boston, Massachusetts.
Maxwell
M M
MM
Brenner
B M
BM
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D016384:Consensus Sequence; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006580:Genetic Carrier Screening; D005938:Glucocorticoids / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D006913:Hydroxysteroid Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000201:enzymology / Q000276:immunology; D008099:Liver / Q000201:enzymology / Q000276:immunology; D008285:Major Histocompatibility Complex; D008322:Mammals; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010088:Oxidoreductases; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D017386:Sequence Homology, Amino Acid; D013256:Steroids / Q000378:metabolism*; D014158:Transcription, Genetic
D005938:Glucocorticoids; C079876:H2-Ke6 protein, mouse; D006649:Histocompatibility Antigens; D012333:RNA, Messenger; D013256:Steroids; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D042842:11-beta-Hydroxysteroid Dehydrogenases