Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.

Abstract

Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS) or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development.

• Authors: Yujiro Tanaka, Aya Nakamura, Masaki Suimye Morioka, Shoko Inoue, Mimi Tamamori-Adachi, Kazuhiko Yamada, Kenji Taketani, Junya Kawauchi, Miki Tanaka-Okamoto, Jun Miyoshi, Hiroshi Tanaka, Shigetaka Kitajima
• Journal: PloS one (PLoS One) Vol. 6 Issue 10 Pg. e26848 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22046379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF3 protein, human
• Activating Transcription Factor 3
• Apoptosis Regulatory Proteins
• TP53 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53

Topics

• Activating Transcription Factor 3 (genetics)
• Apoptosis (genetics)
• Apoptosis Regulatory Proteins (genetics)
• Cell Line, Tumor
• DNA Damage (genetics)
• Gene Regulatory Networks
• Humans
• Male
• Neoplasms (genetics, metabolism)
• Oxidative Stress (genetics)
• Transcription Factors (genetics)
• Tumor Suppressor Protein p53 (metabolism)