Activation of the murine type II transforming growth factor-beta receptor gene: up-regulation and function of the transcription factor Elf-3/Ert/Esx/Ese-1.
Previous studies demonstrated that differentiation of mouse embryonal carcinoma cells leads to transcriptional up-regulation of the mouse type II transforming growth factor-beta receptor (mTbetaR-II) gene. To elucidate the molecular mechanisms regulating transcription of this gene, we isolated the 5'-flanking region of the mTbetaR-II gene and characterized its expression in F9-differentiated cells. Analysis of mTbetaR-II promoter/reporter gene constructs demonstrates that two conserved Ets-binding sites play an important role in the activity of the mTbetaR-II promoter. Importantly, we present evidence that mElf-3, a member of the Ets family, plays a key role in the activation of the mTbetaR-II promoter. Northern blot analysis reveals that the steady-state levels of mTbetaR-II mRNA increase in parallel with those of mElf-3 mRNA during the differentiation of F9 embryonal carcinoma cells. We also demonstrate that mElf-3 contains one or more domains that influence its binding to DNA. Finally, we report that a single amino acid substitution in the transactivation domain of mElf-3 reduces its ability to transactivate and elevates its steady-state levels of expression. In conclusion, our data argue that mElf-3 plays a key role in the regulation of the mTbetaR-II gene, and Elf-3 itself is regulated at multiple levels.
Kim
Jae-Hwan
JH
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Wilder
Phillip J
PJ
Hou
Jingwen
J
Nowling
Tamara
T
Rizzino
Angie
A
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II