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Published on: August 19, 2014
Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice
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.
Insights
Activating transcription factor 3 (ATF3) is crucial for maintaining genome stability and suppressing early cancer development. ATF3 deficiency in mice leads to spontaneous tumors and genomic instability, highlighting its role in tumor suppression.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Mice lacking DNA-damage response (DDR) genes are prone to tumors due to genomic instability.
- Activating transcription factor 3 (ATF3), a stress sensor, activates p53 and its target genes upon DNA damage.
Purpose of the Study:
- To investigate the role of ATF3 in maintaining genome stability and suppressing tumor development.
- To determine if ATF3 contributes to tumor suppression through p53 activation.
Main Methods:
- Generated and analyzed Atf3-deficient (Atf3-/-) mice and wild-type (Atf3+/+) littermates.
- Assessed chromosomal stability in Atf3-/- mouse embryonic fibroblasts (MEFs).
- Examined tumor development in Atf3-/- mice, and in combination with Trp53+/- or Trp53-/- backgrounds.
Main Results:
- Atf3-/- mice developed spontaneous tumors and had reduced lifespan compared to wild-type mice.
- Atf3-/- MEFs exhibited increased chromosomal aberrations and micronuclei, indicating genetic instability.
- ATF3 deficiency promoted p53 activation and apoptosis in mouse tissues, and its absence exacerbated tumorigenesis in Trp53+/- mice.
Conclusions:
- ATF3 plays a critical role in maintaining genome integrity and suppressing early cancer development.
- The tumor suppressive function of ATF3 is significantly dependent on its regulation of p53.
- These findings establish ATF3 as a key genetic factor in preventing spontaneous tumorigenesis.
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