title: Regulation of p53 during senescence in normal human keratinocytes.
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 (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 p16(INK4A) , 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.
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.
authors.forename: Reuben H
authors.initials: RH
authors.lastname: Kim
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.
authors.forename: Terresa
authors.initials: T
authors.lastname: Kim
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Yang
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Bae
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.
authors.forename: Drake W
authors.initials: DW
authors.lastname: Williams
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Phung
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.
authors.forename: Ki-Hyuk
authors.initials: KH
authors.lastname: Shin
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Hong
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA, 90095, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.|UCLA David Geffen School of Medicine, Los Angeles, CA, 90095, USA.
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D019175:DNA Methylation; D006657:Histones / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D016159:Tumor Suppressor Protein p53
keywords: aging; cancer; epigenetics; human keratinocytes; p53; replicative senescence