In:
Aging Cell, Wiley, Vol. 14, No. 5 ( 2015-10), p. 838-846
Abstract:
p53, the guardian of the genome, is a tumor suppressor protein and critical for the genomic integrity of the cells. Many studies have shown that intracellular level of p53 is enhanced during replicative senescence in normal fibroblasts, and the enhanced level of p53 is viewed as the cause of senescence. Here, we report that, unlike in normal fibroblasts, the level of intracellular p53 reduces during replicative senescence and oncogene‐induced senescence ( OIS ) in normal human keratinocytes ( NHK s). We found that the intracellular p53 level was also decreased in age‐dependent manner in normal human epithelial tissues. Senescent NHK s exhibited an enhanced level of p16 INK4A , induced G 2 cell cycle arrest, and lowered the p53 expression and transactivation activity. We found that low level of p53 in senescent NHK s was due to reduced transcription of p53. The methylation status at the p53 promoter was not altered during senescence, but senescent NHK s exhibited notably lower level of acetylated histone 3 (H3) at the p53 promoter in comparison with rapidly proliferating cells. Moreover, p53 knockdown in rapidly proliferating NHK s resulted in the disruption of fidelity in repaired DNA . Taken together, our study demonstrates that p53 level is diminished during replicative senescence and OIS and that such diminution is associated with H3 deacetylation at the p53 promoter. The reduced intracellular p53 level in keratinocytes of the elderly could be a contributing factor for more frequent development of epithelial cancer in the elderly because of the loss of genomic integrity of cells.
Type of Medium:
Online Resource
ISSN:
1474-9718
,
1474-9726
DOI:
10.1111/acel.2015.14.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2113083-8
detail.hit.zdb_id:
2099130-7
SSG:
12
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