Cellular Senescence in Mouse Hippocampus After Irradiation and the Role of p53 and p21.
Diverse stress signals including irradiation may trigger cellular senescence. We asked whether irradiation induced senescence in mouse hippocampus, and whether p53 or p21 played a role in this response. Following whole-brain irradiation, polymerase chain reaction (PCR) arrays for senescence-associated genes showed increased expression of CDKN1A (p21) and CDKN2A (p19ARF) in mouse hippocampus at 9 weeks. Upregulation of p21 and p19ARF was confirmed using real-time PCR, which also demonstrated increased CDKN2A/p16INKa expression after irradiation. No altered regulation of another 17 senescence-associated genes was observed after irradiation. Immunohistochemistry revealed increased nuclear expression of p16INK4A, p19ARF, p53, p21, phosphorylated p38 (pp38), 4-hydroxy-2-nonenal, and interleukin-6 (IL6) in granule cells of dentate gyrus after irradiation. Increased p16 nuclear immunoreactivity was further observed in type -1 cells, the putative neural stem cells. γ-phosphorylated-histone-2A nuclear foci were also seen in dentate gyrus 9 weeks postirradiation. In nonirradiated mice knockout of the TRP53 or p21 gene, there was increased p16INK4A, p19ARF, and IL6, but not pp38 in dentate gyrus. We conclude that irradiation induces transcript and protein expression profile alterations in mouse dentate gyrus consistent with the senescence phenotype. Absence of p53 or p21 results in increase in baseline expression of senescence markers with no further increase in expression after irradiation.
University of Toronto, The Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Ontario, Canada.
Zoey
Z
Cheng
University of Toronto, The Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Yan Zhen
YZ
Zheng
University of Toronto, The Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Yu-Qing
YQ
Li
University of Toronto, The Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Ontario, Canada.|Department of Radiation Oncology, University of Toronto, Ontario, Canada.
C Shun
CS
Wong
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects*; D018891:Dentate Gyrus / Q000378:metabolism / Q000528:radiation effects; D006624:Hippocampus / Q000528:radiation effects*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects
D015415:Biomarkers; C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015850:Interleukin-6; C577686:interleukin-6, mouse
Cellular senescence; Hippocampus; Irradiation; Neural stem cells; PCR array; p21; p53