title: Id-1, ITF-2, and Id-2 comprise a network of helix-loop-helix proteins that regulate mammary epithelial cell proliferation, differentiation, and apoptosis.
abstract: Mammary epithelial cells proliferate, invade the stroma, differentiate, and die in adult mammals by mechanisms that are poorly understood. We found that Id-1, an inhibitor of basic helix-loop-helix transcription factors, regulates mammary epithelial cell growth, differentiation, and invasion in culture. Here, we show that Id-1 is expressed highly during mammary development in virgin mice and during early pregnancy, when proliferation and invasion are high. During mid-pregnancy, Id-1 expression declined to undetectable levels as the epithelium differentiated fully. Surprisingly, Id-1 increased during involution, when the epithelium undergoes extensive apoptosis. To determine whether Id-1 regulates both proliferation and apoptosis, we constitutively expressed Id-1 in mammary epithelial cell cultures. Id-1 stimulated proliferation in sparse cultures but induced apoptosis in dense cultures, which reflect epithelial cell density during early pregnancy and involution, respectively. To understand how Id-1 acts, we screened a yeast two-hybrid library from differentiating mammary epithelial cells and identified ITF-2, a basic helix-loop-helix transcription factor, as an Id-1-interacting protein. Overexpression of ITF-2 significantly reduced Id-1-stimulated proliferation and apoptosis. We show further that, in contrast to Id-1, Id-2 was expressed highly in differentiated mammary epithelial cells in vivo and in culture. In culture, Id-2 antisense transcripts blocked differentiation. Our results suggest that Id-1, ITF-2, and Id-2 comprise a network of interacting molecular switches that govern mammary epithelial cell phenotypes.
authors.affiliation: Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco, California 94115, USA.
authors.forename: S
authors.initials: S
authors.lastname: Parrinello
authors.forename: C Q
authors.initials: CQ
authors.lastname: Lin
authors.forename: K
authors.initials: K
authors.lastname: Murata
authors.forename: Y
authors.initials: Y
authors.lastname: Itahana
authors.forename: J
authors.initials: J
authors.lastname: Singh
authors.forename: A
authors.initials: A
authors.lastname: Krtolica
authors.forename: J
authors.initials: J
authors.lastname: Campisi
authors.forename: P Y
authors.initials: PY
authors.lastname: Desprez
mesh_terms: D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D001940:Breast / Q000166:cytology; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D053938:DNA Fragmentation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D015536:Down-Regulation; D004847:Epithelial Cells; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018257:Helix-Loop-Helix Motifs; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors; D013997:Time Factors; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497455:Idb1 protein, mouse; C497452:Idb2 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C090743:Tcf4 protein, mouse; D015534:Trans-Activators; D000073940:Transcription Factor 4; D014157:Transcription Factors