Hoxa5 overexpression correlates with IGFBP1 upregulation and postnatal dwarfism: evidence for an interaction between Hoxa5 and Forkhead box transcription factors.
Transgenic mice expressing the homeobox gene Hoxa5 under the control of Hoxb2 regulatory elements present a growth arrest during weeks two and three of postnatal development, resulting in proportionate dwarfism. These mice present a liver phenotype illustrated by a 12-fold increase in liver insulin-like growth factor binding protein 1 (IGFBP1) mRNA and a 50% decrease in liver insulin-like growth factor 1 (IGF1) mRNA correlated with a 50% decrease in circulating IGF1. We show that the Hoxa5 transgene is expressed in the liver of these mice, leading to an overexpression of total (endogenous plus transgene) Hoxa5 mRNA in this tissue. We have used several cell lines to investigate a possible physiological interaction of Hoxa5 with the main regulator of IGFBP1 promoter activity, the Forkhead box transcription factor FKHR. In HepG2 cells, Hoxa5 has little effect by itself but inhibits the FKHR-dependent activation of the IGFBP1 promoter. In HuF cells, Hoxa5 cooperates with FKHR to dramatically enhance IGFBP1 promoter activity. This context-dependent physiological interaction probably corresponds to the existence of a direct interaction between Hoxa5 and FKHR and FoxA2/HNF3beta, as demonstrated by pull-down experiments achieved either in vitro or after cellular co-expression. In conclusion, we propose that the impaired growth observed in this transgenic line relates to a liver phenotype best explained by a direct interaction between Hoxa5 and liver-specific Forkhead box transcription factors, in particular FKHR but also Foxa2/HNF3beta. Because Hoxa5 and homeogenes of the same paralog group are normally expressed in the liver, the present results raise the possibility that homeoproteins, in addition to their established role during early development, regulate systemic physiological functions.
Foucher
Isabelle
I
CNRS UMR 8542, Ecole normale supérieure, 46 rue d'Ulm, 75230 Paris Cedex 05, France.
Volovitch
Michel
M
Frain
Monique
M
Kim
J Julie
JJ
Souberbielle
Jean-Claude
JC
Gan
Lixia
L
Unterman
Terry G
TG
Prochiantz
Alain
A
Trembleau
Alain
A
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009420:Nervous System / Q000196:embryology*; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C496503:Foxa2 protein, mouse; C467200:Foxo1 protein, mouse; C489213:HOXA5 protein, human; C086061:HOXB2 protein, human; D018398:Homeodomain Proteins; C059637:Hoxa5 protein, mouse; C490111:Hoxb2 protein, mouse; D018970:Insulin-Like Growth Factor Binding Protein 1; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D007334:Insulin-Like Growth Factor I