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Fos-dependent induction of Chk1 protects osteoblasts from replication stress

Jochen Schulze1, Andres J Lopez-Contreras2, Özge Uluçkan1

  • 1BBVA Foundation-CNIO Cancer Cell Biology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.

Cell Cycle (Georgetown, Tex.)
|April 26, 2014
PubMed

Insights

Fos expression in osteoblasts promotes cancer by activating replication stress response pathways, particularly Chk1. This mechanism safeguards genome stability, relevant in oncogene-induced cell proliferation.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Osteosarcomas (OS) develop in mice with stable Fos expression in osteoblasts, but mechanisms are unclear.
  • Fos is implicated in bone development and cancer, but its role in replication stress is unknown.

Purpose of the Study:

  • To elucidate the mechanisms by which Fos expression in osteoblasts leads to osteosarcomas.
  • To identify novel transcriptional targets of Fos in osteoblasts and understand their role in cellular response to replication stress.

Main Methods:

  • A doxycycline-inducible genetic system to control Fos expression in mouse osteoblasts.
  • RNA sequencing and gene set enrichment analysis to identify Fos-regulated genes.
  • Assessing the impact of Fos on replication stress and DNA damage response.

Main Results:

  • Fos expression induces a cellular response to replication stress (RS) in osteoblasts.
  • Fos upregulates the Chk1 kinase, a key suppressor of RS.
  • Fos protects osteoblasts from RS and DNA damage, facilitating oncogene-driven transformation.

Conclusions:

  • Fos has a novel role in protecting genome stability during replication by upregulating Chk1.
  • This function of Fos is crucial in contexts of oncogene-induced S-phase entry and osteosarcoma development.
Keywords:
AP-1Chk1DNA damageFososteoblastosteosarcomareplication stress

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