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PMID: 8114709 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

YY1 represses beta-casein gene expression by preventing the formation of a lactation-associated complex.

Molecular and cellular biology ·Vol. 14 ·No. 3 ·1994-03-00 ·Pages 1752-63

Raught B, Khursheed B, Kazansky A, Rosen J

Abstract

Site-specific mutagenesis of the highly conserved milk box (-140 to -110) region suggested that beta-casein expression is regulated by a hormone-mediated relief of repression (M. Schmitt-Ney, W. Doppler, R. K. Ball, and B. Groner, Mol. Cell. Biol. 11:3745-3755, 1991). However, when this sequence was placed upstream of a heterologous thymidine kinase promoter, it activated reporter gene expression. This apparent paradox was resolved when the trans-acting factor YY1, capable of acting as both a positive and negative regulator, was shown to interact with the milk box region, using bacterially expressed YY1 and specific oligonucleotide and antibody competition experiments. Second, it was demonstrated that extracts prepared from several cell types contained a protein(s) interacting with the mammary gland-specific factor (MGF) binding site, previously shown to be required for beta-casein promoter activity (Schmitt-Ney et al., Mol. Cell. Biol. 11:3745-3755, 1991). Sequence analysis of this site revealed similarity to the gamma interferon-activated sequence, suggesting that MGF may be related to the stat91 signaling protein. Finally, using an oligonucleotide encompassing both the YY1 and MGF sites, we detected a slow-mobility complex only in extracts from mammary glands at late pregnancy and lactation (lactation-associated complex [LAC]). Site-specific mutation of the YY1 binding site led to an enhancement in LAC DNA binding activity, while mutation of the MGF site decreased detectable LAC. These results support a model in which lactogenic stimuli lead to a decrease in YY1 binding, and subsequent increased formation of LAC at a nearby binding site, to stimulate beta-casein transcription.

MeSH Terms
Animals Base Sequence Binding Sites Caseins/genetics Cells, Cultured Consensus Sequence DNA-Binding Proteins/genetics Erythroid-Specific DNA-Binding Factors Gene Expression Lactation Macromolecular Substances Mammary Glands, Animal/physiology Molecular Sequence Data Oligodeoxyribonucleotides/chemistry Prolactin/pharmacology Promoter Regions, Genetic RNA, Messenger/genetics Rats Repressor Proteins/genetics Sequence Alignment Sequence Homology, Nucleic Acid Transcription Factors/genetics YY1 Transcription Factor
Chemicals
Caseins DNA-Binding Proteins Erythroid-Specific DNA-Binding Factors Macromolecular Substances Oligodeoxyribonucleotides RNA, Messenger Repressor Proteins Transcription Factors YY1 Transcription Factor Yy1 protein, rat Prolactin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Raught B
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.
Khursheed B
Kazansky A
Rosen J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.14.3.1752-1763.1994
Published
1994-03-00
Pages
1752-63
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC358533
Subset
IM
Grants
NCI NIH HHS · CA16303 · United States
External Links
PubMed source DOI: 10.1128/mcb.14.3.1752-1763.1994 PMC Full Text View journal details
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