Identification of a novel zinc finger protein binding a conserved element critical for Pit-1-dependent growth hormone gene expression.
The growth hormone (GH) and prolactin genes require the pituitary-specific POU domain transcription factor Pit-1 for their activation. However, additional factors are necessary for the effective expression of these genes. Analysis of evolutionarily conserved sequences in the proximal GH promoter suggests the critical importance of one highly conserved element located between the two Pit-1 response elements. Mutation of this site decreases expression of a transgene in mice > 100-fold. We have identified a major activity binding to this site as a novel member of the Cys/His zinc finger superfamily, referred to as Zn-15. The Zn-15 DNA-binding domain comprises three zinc fingers separated by unusually long linker sequences that would be expected to interrupt specific DNA site recognition. Zn-15 synergizes with Pit-1 to activate the GH promoter in heterologous cell lines in which this promoter is only minimally responsive to Pit-1 alone. Our data suggest that functional interactions between the tissue-specific POU domain factor Pit-1 and this novel zinc finger factor binding to an evolutionarily conserved region in the GH promoter may constitute an important component of the combinatorial code that underlies the effective expression of the GH gene.
Lipkin
S M
SM
Eukaryotic Regulatory Biology Program, University of California, San Diego, La Jolla 92093-0648.
Näär
A M
AM
Kalla
K A
KA
Sack
R A
RA
Rosenfeld
M G
MG
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D013006:Growth Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D011401:Promoter Regions, Genetic; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000378:metabolism*; D016335:Zinc Fingers
D004247:DNA; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D015534:Trans-Activators; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494187:POU1F1 protein, human; C494185:Pou1f1 protein, mouse; C494186:Pou1f1 protein, rat; C406423:Zfp292 protein, mouse; C489979:Zfp292 protein, rat