Expression and Role of p53 in the Retina

Vuong, Linda; Conley, Shannon M.; Al‐Ubaidi, Muayyad R.

doi:10.1167/iovs.11-8909

Cited by 41 publications

(32 citation statements)

References 133 publications

(157 reference statements)

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“…Moreover, p53 has been linked to retinal apoptosis in specific cell types. 56 Our p53 siRNA studies further support the participation of p53 signaling in apoptosis of RPE cells. Treatment of aged RPE with p53 siRNA caused a knockdown of p53 expression, leading to a direct decrease in caspase-3 activation and apoptosis (Figs.…”

Section: Discussionsupporting

confidence: 71%

Age-Related Susceptibility to Apoptosis in Human Retinal Pigment Epithelial Cells Is Triggered by Disruption of p53–Mdm2 Association

Bhattacharya¹,

Chaum

Johnson

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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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. (Invest Ophthalmol Vis Sci. 2012;53:8350-8366) DOI:10.1167/ iovs.12-10495 A major challenge in vision research is the identification of the causative factors that lead to declines in retinal function that will ultimately result in age-related macular degeneration (AMD) for a projected 3 million individuals in the United States with neovascular AMD and/or geographic atrophy by 2020. 1 One promising strategy in understanding this multifactorial disease process is to identify and track agedependent changes in cellular pathways, especially in cells of the retinal pigment epithelium (RPE) because these represent the gatekeepers whose loss of functional integrity has been linked to retinal aging.2-4 RPE cells constitute a major component of the blood-retinal barrier (BRB) and loss of integrity of tight junctions (TJs) and adherens junctions (AJs) in RPE can disrupt photoreceptor homeostasis. 5-9 RPE cells also phagocytosize tips of outer segments normally shed by photoreceptors, generate melanosomes to function as a light and heat sink, provide trophic factors, and recycle visual pigments. Many of the hallmarks of AMD reflect malfunctions of these RPE-related pathways, including photobleaching of melanosomes, accumulation of lipofuscin granules, impairment of outer segment phagocytosis, formation of drusen, and breakdown of the BRB in a...

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Section: Discussionsupporting

confidence: 71%

Age-Related Susceptibility to Apoptosis in Human Retinal Pigment Epithelial Cells Is Triggered by Disruption of p53–Mdm2 Association

Bhattacharya¹,

Chaum

Johnson

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…In addition, liraglutide was able to prevent the diabetes-induced increase of caspase-8 and the Bax (proapoptotic)/Bcl-xL (antiapoptotic) ratio. In addition, we found that liraglutide (systemically and topically administered) was able to prevent the diabetes-induced retinal activation of p53, a factor that participates in hypoxic and oxidative stress-mediated retinal cell death (38), as well as several key molecules involved in retinal apoptosis and inflammation such as FasL and iNOS (39)(40)(41).…”

Section: Discussionmentioning

confidence: 90%

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

et al. 2015

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Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Since glucagonlike peptide 1 (GLP-1) exerts neuroprotective effects in the central nervous system and the retina is ontogenically a brain-derived tissue, the aims of the current study were as follows: 1) to examine the expression and content of GLP-1 receptor (GLP-1R) in human and db/db mice retinas; 2) to determine the retinal neuroprotective effects of systemic and topical administration (eye drops) of GLP-1R agonists in db/db mice; and 3) to examine the underlying neuroprotective mechanisms. We have found abundant expression of GLP-1R in the human retina and retinas from db/db mice. Moreover, we have demonstrated that systemic administration of a GLP-1R agonist (liraglutide) prevents retinal neurodegeneration (glial activation, neural apoptosis, and electroretinographical abnormalities). This effect can be attributed to a significant reduction of extracellular glutamate and an increase of prosurvival signaling pathways. We have found a similar neuroprotective effect using topical administration of native GLP-1 and several GLP-1R agonists (liraglutide, lixisenatide, and exenatide). Notably, this neuroprotective action was observed without any reduction in blood glucose levels. These results suggest that GLP-1R activation itself prevents retinal neurodegeneration. Our results should open up a new approach in the treatment of the early stages of DR.

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“…For example, it seems that Trim39 contributes more significantly than MDM2 to cell growth and p53 stability in hTERT-RPE cells. This may be of potential significance for diseases of the retina, for example, macular degeneration, where p53 is important for controlling cell death in response to oxidative stress (25).…”

Section: Resultsmentioning

confidence: 99%

Ubiquitylation of p53 by the APC/C inhibitor Trim39

Zhang

Huang

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.

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Expression and Role of p53 in the Retina

Cited by 41 publications

References 133 publications

Age-Related Susceptibility to Apoptosis in Human Retinal Pigment Epithelial Cells Is Triggered by Disruption of p53–Mdm2 Association

Age-Related Susceptibility to Apoptosis in Human Retinal Pigment Epithelial Cells Is Triggered by Disruption of p53–Mdm2 Association

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

Ubiquitylation of p53 by the APC/C inhibitor Trim39

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