title: Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo.
abstract: Studies suggest that Hsf4 expression correlates with its role in cell growth and differentiation. However, the role of Hsf4 in tumorigenesis in vivo remains unexplored. In this article, we provide evidence that absence of the Hsf4 gene suppresses evolution of spontaneous tumors arising in p53- or Arf-deficient mice. Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes. Using mouse embryo fibroblasts deficient in the hsf4 gene, we have found that these cells exhibit reduced proliferation that is associated with induction of senescence and senescence-associated β-galactosidase (SA-β-gal). Cellular senescence in hsf4-deficient cells is associated with the increased expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins. Consistent with the cellular senescence observed in vitro, specific normal tissues of hsf4(-/-) mice and tumors that arose in mice deficient in both hsf4 and p53 genes exhibit increased SA-β-gal activity and elevated levels of p27 compared with wild-type mice. These results suggest that hsf4 deletion-induced senescence is also present in vivo. Our results therefore indicate that Hsf4 is involved in modulation of cellular senescence, which can be exploited during cancer therapy.
authors.affiliation: Charlie Norwood VA Medical Center, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
authors.forename: Xiongjie
authors.initials: X
authors.lastname: Jin
authors.forename: Binnur
authors.initials: B
authors.lastname: Eroglu
authors.forename: Wonkyoung
authors.initials: W
authors.lastname: Cho
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Demetrius
authors.initials: D
authors.lastname: Moskophidis
authors.forename: Nahid F
authors.initials: NF
authors.lastname: Mivechi
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D000076249:Heat Shock Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C484462:Hsf4 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53