Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression.
The growth inhibitory cytokine TGF-beta enforces homeostasis of epithelia by activating processes such as cell cycle arrest and apoptosis. Id2 expression is often highest in proliferating epithelial cells and declines during differentiation. Recently, Id2 expression has been found to depend on Myc-Max transcriptional complexes. We observed that TGF-beta signaling inhibits Id2 expression in human and mouse epithelial cell lines from different tissue origins. Furthermore, the observed Id2 down-regulation by TGF-beta in mouse mammary epithelial cells occurs without a concurrent drop in c-Myc levels. However, sustained Id2 repression in these cells and in human keratinocytes coincides with induction of the Myc antagonistic repressors Mad2 and Mad4, decreased formation of Myc-Max heterodimers and the replacement of Myc-Max complexes with Mad-Max complexes on the Id2 promoter. These results argue that induction of Mad expression and Id2 down-regulation are important events during the TGF-beta cytostatic program in epithelial cells.
Siegel
Peter M
PM
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Shu
Weiping
W
Massagué
Joan
J
D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002843:Chromatin / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D019281:Dimerization; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000187:drug effects; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002843:Chromatin; D017931:DNA Primers; D004268:DNA-Binding Proteins; C497450:ID2 protein, human; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; C079439:MXD1 protein, human; C499479:Mad protein, mouse; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta