A HIC-5- and KLF4-dependent Mechanism Transactivates p21Cip1 in Response to Anchorage Loss
| Autor: | Kazunori Mori, Motoko Shibanuma, Yukiko Oshima, Hiroyuki Hamanaka, Kiyoshi Nose, Fumihiro Ishikawa, Yuri Araki |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Transcriptional Activation Kruppel-Like Transcription Factors Biology Models Biological Biochemistry DNA-binding protein Kruppel-Like Factor 4 Mice Transactivation Transcription (biology) Cell Adhesion Animals Humans Molecular Biology Transcription factor Regulation of gene expression Mice Inbred C3H Binding Sites Cell growth HEK 293 cells Intracellular Signaling Peptides and Proteins Signal transducing adaptor protein DNA Cell Biology Fibroblasts LIM Domain Proteins Cell biology DNA-Binding Proteins Cytoskeletal Proteins HEK293 Cells Gene Expression Regulation Protein Binding Subcellular Fractions |
| Zdroj: | Journal of Biological Chemistry. 287:38854-38865 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.377721 |
| Popis: | Anchorage loss elicits a set of responses in cells, such as transcriptional changes, in order to prevent inappropriate cell growth in ectopic environments. However, the mechanisms underlying these responses are poorly understood. In this study, we investigated the transcriptional up-regulation of cyclin-dependent kinase inhibitor p21(Cip1) during anchorage loss, which is important for cell cycle arrest of nonadherent cells in the G1 phase. Up-regulation was mediated by an upstream element, designated as the detachment-responsive element (DRE), that contained Kruppel-like factor 4 (KLF4) and runt-related transcription factor 1 (RUNX1) recognition sites; both of these together were necessary for transactivation, as individually they were insufficient. RNAi experiments revealed that KLF4 and a multidomain adaptor protein, hydrogen peroxide-inducible clone 5 (HIC-5), were critically involved in DRE transactivation. The role of HIC-5 in this mechanism was to tether KLF4 to DNA sites in response to cellular detachment. In addition, further analysis suggested that oligomerization and subsequent nuclear matrix localization of HIC-5, which was accelerated spontaneously in cells during anchorage loss, was assumed to potentiate the scaffolding function of HIC-5 in the nucleus and consequently regulate p21(Cip1) transcription in a manner responding to anchorage loss. At the RUNX1 site, a LIM-only protein, CRP2, imposed negative regulation on transcription, which appeared to be removed by anchorage loss and contributed to increased transcriptional activity of DRE together with regulation at the KLF4 sites. In conclusion, this study revealed a novel transcriptional mechanism that regulated gene expression in a detachment-dependent manner, thereby contributing to anchorage-dependent cell growth. |
| Databáze: | OpenAIRE |
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