Models of insulin action on metabolic and growth response genes.
In ongoing studies aimed at elucidating the mechanism of insulin action on the expression of genes that modulate glucose utilization and cell growth, we have focused on the inductive effect of insulin on transcription of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the early growth response gene, Egr-1. Insulin acutely stimulates the expression of both genes in 3T3 adipocytes; however, in primary adipocytes, chronic insulin exposure has opposing effects on the expression of these genes. GAPDH mRNA is decreased in the epididymal fat cells of diabetic animals and is increased over control levels when insulin is replaced, while Egr-1 mRNA levels are increased in diabetic animals. These observations, coupled with the finding that insulin-stimulated Egr-1 gene transcription is impaired in a Chinese hamster ovarian (CHO) cell line that displays normal metabolic responses but impaired ability to regulate DNA synthesis, support the conclusion that insulin regulation of Egr-1, a growth response gene, and GAPDH, a metabolic response gene, are mediated by distinct pathways. We present evidence that supports the role of protein phosphorylation in mediating the effect of insulin on activation of Egr-1 and GAPDH gene transcription.
Alexander-Bridges
M
M
Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Buggs
C
C
Giere
L
L
Denaro
M
M
Kahn
B
B
White
M
M
Sukhatme
V
V
Nasrin
N
N
D016475:3T3 Cells / Q000187:drug effects; D000273:Adipose Tissue / Q000166:cytology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D051766:Early Growth Response Protein 1; D004822:Epididymis; D005786:Gene Expression Regulation / Q000187:drug effects*; D005796:Genes; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D017874:Immediate-Early Proteins; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D007328:Insulin; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011972:Receptor, Insulin; D000469:Alkaline Phosphatase