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Cell Cycle. 2014;13(12):1980-6. doi: 10.4161/cc.28923. Epub 2014 Apr 24.

Fos-dependent induction of Chk1 protects osteoblasts from replication stress.

Author information

1
BBVA Foundation-CNIO Cancer Cell Biology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
2
Genomic Instability Group; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
3
Bioinformatics Unit; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.

Abstract

Stable Fos expression in the osteoblast lineage results in the development of osteosarcomas (OS) in mice, yet the underlying mechanisms are poorly understood. Using a genetic system in which Fos expression can be induced in osteoblasts in a doxycycline-dependent manner and through subsequent RNA sequencing and gene set enrichment analysis, we were able to identify novel transcriptional targets of Fos in osteoblasts. These included a distinct activation of cellular response toward replication stress (RS), exemplified by a Fos-dependent induction of the RS-suppressing Chk1 kinase. Importantly, Fos expression protects osteoblasts from RS and DNA damage likely through upregulation of Chk1 and facilitates transformation by Ras/E1A oncogenes. These data reveal a novel function of Fos in safeguarding genome stability during replication, which is particularly relevant in conditions of oncogene-induced S-phase entry.

KEYWORDS:

AP-1; Chk1; DNA damage; Fos; osteoblast; osteosarcoma; replication stress

PMID:
24762558
PMCID:
PMC4111761
DOI:
10.4161/cc.28923
[Indexed for MEDLINE]
Free PMC Article
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