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Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.

ABSTRACT: Stress response gene ATF3 plays a pleiotropic role in determining cell fate in response to mitogenic or stress stimuli. An alternate promoter of the human ATF3 gene (designated P1 in this study) has recently been reported, which is located approximately 43.5 kb upstream of the previously reported P2 promoter. We showed here that the P1 promoter is highly conserved between human and mouse and is functional in response to various stimuli, whereas the P1 promoter was dominantly induced by serum and the P2 promoter was more efficiently activated in response to TGF-beta and oncogenic HRAS. The P1 promoter contains multiple transcriptional start sites, and the different 5'-UTRs markedly affected their translation in response to stress. In human prostate and Hodgkin Reed-Sternberg cancer cells with elevated expression of ATF3, the P1 promoter was constitutively activated and its chromatin structure was modified into active configuration. The differential usage of alternate promoters of the ATF3 gene at both transcriptional and translational level and the modification of chromatin structure may provide a novel mechanism for expressing ATF3 in determining cell fate during stress response and cancer.

SUBMITTER: Miyazaki K

PROVIDER: S-EPMC2655689 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.

Miyazaki Keisuke K Inoue Shoko S Yamada Kazuhiko K Watanabe Masashi M Liu Qin Q Watanabe Toshiki T Adachi Mimi Tamamori MT Tanaka Yujiro Y Kitajima Shigetaka S

Nucleic acids research 20090109 5

Stress response gene ATF3 plays a pleiotropic role in determining cell fate in response to mitogenic or stress stimuli. An alternate promoter of the human ATF3 gene (designated P1 in this study) has recently been reported, which is located approximately 43.5 kb upstream of the previously reported P2 promoter. We showed here that the P1 promoter is highly conserved between human and mouse and is functional in response to various stimuli, whereas the P1 promoter was dominantly induced by serum and ...[more]

PMID: 19136462

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Project description:INTRODUCTION:The potential of pluripotent stem cells to be used for cell therapy depends on a comprehensive understanding of the molecular mechanisms underlying their unique ability to specify cells of all germ layers while undergoing unlimited self-renewal. Alternative splicing and alternate promoter selection contribute to this mechanism by increasing the number of transcripts generated from a single gene locus and thus enabling expression of novel protein variants which may differ in their biological role. The homeodomain-containing transcription factor NANOG plays a critical role in maintaining the pluripotency of Embryonic Stem Cells (ESC). Therefore, a thorough understanding of the transcriptional regulation of the NANOG locus in ESCs is necessary. METHODS:Regulatory footprints and transcription levels were identified for NANOG in human embryonic stem cells from data obtained using high-throughput sequencing methodologies. Quantitative real-time PCR following reverse transcription of RNA extracted human ESCs was used to validate the expression of transcripts from a region that extends upstream of the annotated NANOG transcriptional start. Promoter identification and characterization were performed using promoter reporter and electrophoretic mobility shift assays. RESULTS:Transcriptionally active chromatin marking and transcription factor binding site enrichment were observed at a region upstream of the known transcriptional start site of NANOG. Expression of novel transcripts from this transcriptionally active region confirmed the existence of NANOG alternative splicing in human ESCs. We identified an alternate NANOG promoter of significant strength at this upstream region. We also discovered that NANOG autoregulates its expression by binding to its proximal downstream promoter. CONCLUSION:Our study reveals novel transcript expression from NANOG in human ESCs, indicating that alternative splicing increases the diversity of transcripts originating from the NANOG locus and that these transcripts are expressed by an alternate promoter. Alternative splicing and alternate promoter usage collaborate to regulate NANOG, enabling its function in the maintenance of ESCs.

Dataset Information

Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.

Publications

Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.

Similar Datasets

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