RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repair.
Nuclear factor (NF)-kappaB is a positive regulator of tumour development and progression, but how it functions in normal cells leading to oncogenesis is not clear. As cellular senescence has proven to be an intrinsic tumour suppressor mechanism that cells must overcome to establish deregulated growth, we used primary fibroblasts to follow NF-kappaB function in cells transitioning from senescence to subsequent immortalization. Our findings show that RelA/p65(-/-) murine fibroblasts immortalize at considerably faster rates than RelA/p65(+/+) cells. The ability of RelA/p65(-/-) fibroblasts to escape senescence earlier is due to their genomic instability, characterized by high frequencies of DNA mutations, gene deletions and gross chromosomal translocations. This increase in genomic instability is closely related to a compromised DNA repair that occurs in both murine RelA/p65(-/-) fibroblasts and tissues. Significantly, these results can also be duplicated in human fibroblasts lacking NF-kappaB. Altogether, our findings present a fresh perspective on the role of NF-kappaB as a tumour suppressor, which acts in pre-neoplastic cells to maintain cellular senescence by promoting DNA repair and genomic stability.
Wang
Jingxin
J
Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210, USA.
Jacob
Naduparambil K
NK
Ladner
Katherine J
KJ
Beg
Amer
A
Perko
James D
JD
Tanner
Stephan M
SM
Liyanarachchi
Sandya
S
Fishel
Richard
R
Guttridge
Denis C
DC
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D004247:DNA / Q000235:genetics; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D042822:Genomic Instability; D006861:Hydrogen Peroxide / Q000737:chemistry; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014178:Translocation, Genetic
D016328:NF-kappa B; D051996:Transcription Factor RelA; D004247:DNA; D006861:Hydrogen Peroxide