title: Increased FOXM1 expression can stimulate DNA repair in normal hepatocytes in vivo but also increases nuclear foci associated with senescence.
abstract: OBJECTIVE
  FOXM1 is a transcription factor that has been shown to promote cell proliferation in many tissues during early development and high cell turnover tissues in adults. In a number of tumour cell lines, enrichment of FOXM1 has been shown to reduce the DNA damage response (DDR) and induction of senescence by a range of DNA-damaging agents, suggesting a role for the protein in DNA repair. Endogenous FOXM1 is expressed at detectable levels in hepatocytes of mice up to 2 weeks of age, but not in older mice. The aim of this investigation has been to better understand the role of the protein in DDR in normal cells in vivo.
  
  
  METHODS
  Mice with artificially prolonged elevated FOXM1 expression in hepatocytes, were exposed to alkylating diethylnitrosamine.
  
  
  RESULTS
  FOXM1-enriched mice had dampened DDR after treatment with this alkylating agent, which was consistent with observed increase in expression of genes involved in DNA repair. Paradoxically, mice with FOXM1 expression, within weeks after exposure to the DNA-damaging agent, had increased levels of potentially senescent hepatocytes with large nuclear foci, containing 53BP1. Similarly, spontaneous accumulation of these cells seen with normal ageing in mice was increased with FOXM1 enrichment.
  
  
  CONCLUSIONS
  Despite its known abilities to promote proliferation and DNA repair, and to reduce ROS, enrichment of FOXM1, as with other oncoproteins, may cause increased persistent DNA lesions and/or senescence in normal murine hepatocytes.
authors.affiliation: Department of Oral Medicine and Oral Diagnostics, Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, IL, 60612-7213, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Baranski
authors.forename: V V
authors.initials: VV
authors.lastname: Kalinichenko
authors.forename: G R
authors.initials: GR
authors.lastname: Adami
mesh_terms: D000375:Aging; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D004260:DNA Repair; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse