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Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153

Journal article
Authors Alexandra Jauhiainen
Christer Thomsen
Linda Strömbom
Pernilla Grundevik
Carola Andersson
Anna Danielsson
Mattias K Andersson
Olle Nerman
Linda Rörkvist
Anders Ståhlberg
Pierre Åman
Published in PLoS ONE
Volume 7
Issue 4
Pages e33208
ISSN 1932-6203
Publication year 2012
Published at Institute of Clinical Sciences, Department of Oncology
Institute of Biomedicine, Department of Pathology
Department of Mathematical Sciences, Mathematical Statistics
Pages e33208
Language en
Links dx.doi.org/10.1371/journal.pone.003...
https://gup.ub.gu.se/file/89853
Keywords Antineoplastic Agents, Hormonal, pharmacology, Blotting, Western, Cell Adhesion, Cell Cycle, Cell Movement, Cell Nucleus, drug effects, genetics, metabolism, Cell Proliferation, Cells, Cultured, Cytoplasm, drug effects, metabolism, Fibroblasts, cytology, drug effects, metabolism, Fibrosarcoma, drug therapy, genetics, metabolism, Flow Cytometry, Gene Expression Profiling, Green Fluorescent Proteins, genetics, Humans, Liposarcoma, drug therapy, genetics, metabolism, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, genetics, RNA, Messenger, genetics, Real-Time Polymerase Chain Reaction, Recombinant Proteins, genetics, metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tamoxifen, pharmacology, Transcription Factor CHOP, genetics, metabolism, Tumor Markers, Biological, genetics, metabolism
Subject categories Cancer and Oncology, Medical Biotechnology

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.

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