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Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice

Oncogene volume 37, pages 18–27 (2018)Cite this article

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Abstract

Mice lacking genes involving in the DNA-damage response (DDR) are often tumor prone owing to genome instability caused by oncogenic challenges. Previous studies demonstrate that activating transcription factor 3 (ATF3), a common stress sensor, can activate the tumor suppressor p53 and regulate expression of p53 target genes upon DNA damage. However, whether ATF3 contributes to the maintenance of genome stability and tumor suppression remains unknown. Here we report that Atf3-deficient (Atf3−/−) mice developed spontaneous tumors, and died significantly earlier than wild-type (Atf3+/+) mice. Consistent with these results, Atf3−/− mouse embryonic fibroblasts (MEFs) had more aberrant chromosomes and micronuclei, and were genetically unstable. Whereas we demonstrated that ATF3 activated p53 and promoted its pro-apoptotic activity in mouse thymi and small intestines, the chromosomal instability caused by Atf3 deficiency was largely dependent on the regulation of p53 by ATF3. Interestingly, loss of Atf3 also promoted spontaneous tumorigenesis in Trp53+/− mice, but did not affect tumor formation in Trp53−/− mice. Our results thus provide the first genetic evidence linking ATF3 to the suppression of the early development of cancer, and underscore the importance of ATF3 in the maintenance of genome integrity.

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Acknowledgements

This work was supported by the NIH grant R01CA139107 to CY, and the grants from the National Science Foundation of China (81472178) and the State 973 Program of China (2014CB542005) to WD.

Author contributions

ZY, YH and HY bred the mice and carried out histopathological examinations of tumor sections supervised by RK, WD and CY. LL isolated MEFs and prepared slides for cytogenetic analysis. ZY and YH carried out immunohistochemical and immunofluorescence staining with the help of JZ and HD. TH provided the ATF3 −/− mice. BJ, JZ and HD edited the manuscript. CY and WD conceived the study and analyzed the data. CY wrote the manuscript.

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Author notes

  1. Z Wang and Y He: These two authors contributed equally to this work.

Authors and Affiliations

  1. Georgia Cancer Center, Augusta University, Augusta, GA, USA

    Z Wang, Y He, L Lang, H Yang, H-F Ding & C Yan

  2. State Key Laboratory of Oncology in South China, Collaboration Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China

    W Deng

  3. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China

    B Jin

  4. Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    R Kolhe & H-F Ding

  5. Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, USA

    J Zhang

  6. Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH, USA

    T Hai

  7. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    C Yan

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  1. Z Wang
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Wang, Z., He, Y., Deng, W. et al. Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice. Oncogene 37, 18–27 (2018). https://doi.org/10.1038/onc.2017.310

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