Regulation of p53 during senescence in normal human keratinocytes

Summary 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...

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Bibliographic Details
Published in:Aging cell 2015-10, Vol.14 (5), p.838-846
Main Authors: Kim, Reuben H., Kang, Mo K., Kim, Terresa, Yang, Paul, Bae, Susan, Williams, Drake W., Phung, Samantha, Shin, Ki‐Hyuk, Hong, Christine, Park, No‐Hee
Format: Article
Language:English
Subjects:
aging
Analysis
cancer
Cell cycle
Cell Proliferation
Cells, Cultured
Cellular Senescence
Development and progression
DNA Methylation
epigenetics
Fibroblasts
Histones - metabolism
human keratinocytes
Humans
Keratinocytes - cytology
Keratinocytes - metabolism
Methylation
Original
p53
replicative senescence
Senescence
Tumor proteins
Tumor Suppressor Protein p53 - deficiency
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:Summary 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 (NHKs). We found that the intracellular p53 level was also decreased in age‐dependent manner in normal human epithelial tissues. Senescent NHKs exhibited an enhanced level of p16INK4A, induced G2 cell cycle arrest, and lowered the p53 expression and transactivation activity. We found that low level of p53 in senescent NHKs was due to reduced transcription of p53. The methylation status at the p53 promoter was not altered during senescence, but senescent NHKs 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 NHKs 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.
ISSN:1474-9718
1474-9726
DOI:10.1111/acel.12364