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Hepatic Nuclear Factor 3 and High Mobility Group I/Y Proteins Bind the Insulin Response Element of the Insulin-Like Growth Factor-Binding Protein-1 Promoter1
The insulin response element (IRE) of the human insulin-like growth
factor-binding protein-1 (IGFBP-1) promoter contains a palindrome of
the T(A/G)TTT sequence crucial to hormonal regulation of many genes. In
initial studies of how this IRE participates in hormonal regulation,
the electromobility shift assay was used under a variety of conditions
to identify IRE-binding proteins. An exhaustive search identified five
proteins that specifically bind this IRE; purified proteins were used
to show that all five are related to either the high mobility group I/Y
(HMGI/Y) or hepatic nuclear factor 3 (HNF3) protein families. Further
studies used purified HNF3 and HMGI proteins to show: 1) each protects
the IGFBP-1 IRE from deoxyribonuclease I (DNaseI) digestion; and 2)
HNF3 but not HMGI/Y binds to the related phosphoenolpyruvate
carboxykinase and Apo CIII IREs. A series of IRE mutants with variable
responsiveness to insulin were used to show that the presence of a
TGTTT sequence in the mutants did parallel, but HMGI/Y and HNF3 binding
to the mutants did not parallel, the ability of the mutants to confer
the inhibitory effect of insulin. In contrast, HNF3 binding to these
IRE mutants roughly correlates with response of the mutants to
glucocorticoids. The way by which HNF3 and/or other as yet unidentified
IRE-binding proteins confer insulin inhibition to IGFBP-1 transcription
and the role of HMGI/Y in IRE function have yet to be established.