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PMID:22496745

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Citation

Jauhiainen, A, Thomsen, C, Strömbom, L, Grundevik, P, Andersson, C, Danielsson, A, Andersson, MK, Nerman, O, Rörkvist, L, Ståhlberg, A and Åman, P (2012) Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153. PLoS ONE 7:e33208

Abstract

DDIT3, also known as GADD153 or CHOP, encodes a basic leucine zipper transcription factor of the dimer forming C/EBP family. DDIT3 is known as a key regulator of cellular stress response, but its target genes and functions are not well characterized. Here, we applied a genome wide microarray based expression analysis to identify DDIT3 target genes and functions. By analyzing cells carrying tamoxifen inducible DDIT3 expression constructs we show distinct gene expression profiles for cells with cytoplasmic and nuclear localized DDIT3. Of 175 target genes identified only 3 were regulated by DDIT3 in both cellular localizations. More than two thirds of the genes were downregulated, supporting a role for DDIT3 as a dominant negative factor that could act by either cytoplasmic or nuclear sequestration of dimer forming transcription factor partners. Functional annotation of target genes showed cell migration, proliferation and apoptosis/survival as the most affected categories. Cytoplasmic DDIT3 affected more migration associated genes, while nuclear DDIT3 regulated more cell cycle controlling genes. Cell culture experiments confirmed that cytoplasmic DDIT3 inhibited migration, while nuclear DDIT3 caused a G1 cell cycle arrest. Promoters of target genes showed no common sequence motifs, reflecting that DDIT3 forms heterodimers with several alternative transcription factors that bind to different motifs. We conclude that expression of cytoplasmic DDIT3 regulated 94 genes. Nuclear translocation of DDIT3 regulated 81 additional genes linked to functions already affected by cytoplasmic DDIT3. Characterization of DDIT3 regulated functions helps understanding its role in stress response and involvement in cancer and degenerative disorders.

Links

PubMed PMC3322118 Online version:10.1371/journal.pone.0033208

Keywords

Antineoplastic Agents, Hormonal/pharmacology; Blotting, Western; Cell Adhesion; Cell Cycle; Cell Movement; Cell Nucleus/drug effects; Cell Nucleus/genetics; Cell Nucleus/metabolism; Cell Proliferation; Cells, Cultured; Cytoplasm/drug effects; Cytoplasm/metabolism; Fibroblasts/cytology; Fibroblasts/drug effects; Fibroblasts/metabolism; Fibrosarcoma/drug therapy; Fibrosarcoma/genetics; Fibrosarcoma/metabolism; Flow Cytometry; Gene Expression Profiling; Green Fluorescent Proteins/genetics; Humans; Liposarcoma/drug therapy; Liposarcoma/genetics; Liposarcoma/metabolism; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic/genetics; RNA, Messenger/genetics; Real-Time Polymerase Chain Reaction; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tamoxifen/pharmacology; Transcription Factor CHOP/genetics; Transcription Factor CHOP/metabolism; Tumor Markers, Biological/genetics; Tumor Markers, Biological/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DDIT3

GO:0007050: cell cycle arrest

ECO:0000314:

P

Figure 4 shows an assay of cells subjected to the condition of DDIT3 within the cytoplasm or the nucleus. After the cells were cultured for 12 hours, the nuclei were extracted and the gene expression pattern was analyzed. When DDIT3 is present in the nucleus, a much greater portion of cells accumulate in the G1 phase expression pattern, indicating that DDIT3 being present in the nucleus encourages cell cycle arrest in G1.

complete
CACAO 4646

HUMAN:DDIT3

involved_in

GO:0007050: cell cycle arrest

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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