Human diabetes associated with defects in nuclear regulatory proteins for the insulin receptor gene.
The control of gene transcription is mediated by sequence-specific DNA-binding proteins (trans-acting factors) that bind to upstream regulatory elements (cis elements). We have previously identified two DNA-binding proteins that specifically interact with two unique AT-rich sequences of the 5' regulatory region of the insulin receptor gene which have in vivo promoter activity. Herein we have investigated the expression of these DNA-binding proteins in cells from two unrelated patients with insulin resistance and non-insulin-dependent diabetes mellitus. In these patients, the insulin receptor gene was normal. In EBV-transformed lymphoblasts from both patients, insulin receptor mRNA levels and insulin receptor expression were decreased. The expression of nuclear-binding proteins for the 5' regulatory region of the insulin receptor gene was markedly reduced, and this defect paralleled the decrease in insulin receptor protein expression. These studies indicate that DNA-binding proteins to the regulatory region of the insulin receptor gene are important for expression of the insulin receptor. Further, they suggest that in affected individuals, defects in the expression of these proteins may cause decreased insulin receptor expression and insulin resistance.
Cattedra di Endocrinologia, Università degil Studi di Reggio Calabria, Facoltà di Medicina e Chirurgia, Catanzaro, Italy.
A
A
Brunetti
L
L
Brunetti
D
D
Foti
D
D
Accili
I D
ID
Goldfine
D002457:Cell Extracts; D002461:Cell Line, Transformed; D002648:Child; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D051863:Host Cell Factor C1; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D002457:Cell Extracts; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D007328:Insulin; D016328:NF-kappa B; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D004247:DNA; D011972:Receptor, Insulin