Age-related susceptibility to apoptosis in human retinal pigment epithelial cells is triggered by disruption of p53-Mdm2 association.

Bhattacharya S, Chaum E, Johnson DA, Johnson LR
Invest Ophthalmol Vis Sci. 2012 53 (13): 8350-66

PMID: 23139272 · PMCID: PMC4113331 · DOI:10.1167/iovs.12-10495

PURPOSE - Relatively little is known about the contribution of p53/Mdm2 pathway in apoptosis of retinal pigment epithelial (RPE) cells or its possible link to dysfunction of aging RPE or to related blinding disorders such as age-related macular degeneration (AMD).

METHODS - Age-associated changes in p53 activation were evaluated in primary RPE cultures from human donor eyes of various ages. Apoptosis was evaluated by activation of caspases and DNA fragmentation. Gene-specific small interfering RNA was used to knock down expression of p53.

RESULTS - We observed that the basal rate of p53-dependent apoptosis increased in an age-dependent manner in human RPE. The age-dependent increase in apoptosis was linked to alterations in several aspects of the p53 pathway. p53 phosphorylation Ser15 was increased through the stimulation of ATM-Ser1981. p53 acetylation Lys379 was increased through the inhibition of SIRT1/2. These two posttranslational modifications of p53 blocked the sequestration of p53 by Mdm2, thus resulting in an increase in free p53 and of p53 stimulation of apoptosis through increased expression of PUMA (p53 upregulated modulator of apoptosis) and activation of caspase-3. Aged RPE also had reduced expression of antiapoptotic Bcl-2, which contributed to the increase in apoptosis. Of particular interest in these studies was that pharmacologic treatments to block p53 phosphorylation, acetylation, or expression were able to protect RPE cells from apoptosis.

CONCLUSIONS - Our studies suggest that aging in the RPE leads to alterations of specific checkpoints in the apoptotic pathway, which may represent important molecular targets for the treatment of RPE-related aging disorders such as AMD.

MeSH Terms (30)

Acetylation Adult Aged Aged, 80 and over Aging Apoptosis Apoptosis Regulatory Proteins Benzamides Blotting, Western Caspase 3 Cell Proliferation Cells, Cultured Disease Susceptibility DNA Fragmentation Enzyme-Linked Immunosorbent Assay Fluorescent Antibody Technique, Indirect Humans Imidazoles In Situ Nick-End Labeling Middle Aged Naphthols Phosphorylation Piperazines Proto-Oncogene Proteins Proto-Oncogene Proteins c-mdm2 Retinal Pigment Epithelium RNA, Small Interfering Sirtuin 1 Sirtuin 2 Tumor Suppressor Protein p53

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