Telomeres, p21 and the cancer-aging hypothesis

Bell, Jessica F.; Sharpless, Norman E.

doi:10.1038/ng0107-11

Cited by 17 publications

(15 citation statements)

References 14 publications

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“…p21 may facilitate tumor invasion and metastasis possibly through p21-activated kinase-1 ( PAK1 ) (7-9). In addition, p21 has been related with cellular senescence and aging of stem cells (10-12). Thus, it is plausible that the influence of p21 loss on tumor behavior may be modified by cellular energy balance and patient age.…”

Section: Introductionmentioning

confidence: 99%

p21 Expression in Colon Cancer and Modifying Effects of Patient Age and Body Mass Index on Prognosis

Ogino

Nosho

Shima

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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p21 (Cyclin-dependent kinase inhibitor-1A, CDKN1A or CIP1) plays a role in regulating cell cycle, and its expression is lost in most colorectal cancers. p21 Is related with energy balance status, cellular senescence, and stem cell aging. Thus, the influence of p21 loss on tumor behavior and clinical outcome may be modified by patient age and body mass index (BMI). Using 647 colon cancers in two independent prospective cohorts, p21 loss was observed in 509 (79%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratio (HR) for death, adjusted for potential confounders, including p53, cyclin D1, KRAS, BRAF, PIK3CA, LINE-1 hypomethylation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI). p21 Loss was independently associated with low colon cancer-specific mortality [HR, 0.58; 95% confidence interval (95% CI), 0.38-0.89; adjusted for the covariates including MSI, CIMP, and LINE-1 methylation]. The prognostic effect of p21 loss differed significantly by age at diagnosis (P interaction < 0.0001) and BMI (P interaction = 0.002). The adjusted HR for cancer-specific mortality (p21 loss versus p21 expression) was 4.09 (95% CI, 1.13-14.9) among patients <60 year old and 0.37 (95% CI, 0.24-0.59) among patients ≥60 year old. The adverse prognostic effect of obesity was limited to p21-expressing cases (adjusted HR, 5.85; 95% CI, 2.28-15.0; BMI, ≥30 versus <30 kg/m 2 ), but no such effect was observed among p21-lost cases. In conclusion, p21 loss in colon cancer is associated with longer survival among patients ≥60 year old, whereas it is associated with shorter survival among patients <60 year old. Patient BMI also differentially influences prognosis according to p21 CDKN1A status. Our data suggest host-tumor interactions influencing tumor aggressiveness. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2513-21)

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Section: Introductionmentioning

confidence: 99%

p21 Expression in Colon Cancer and Modifying Effects of Patient Age and Body Mass Index on Prognosis

Ogino

Nosho

Shima

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…To investigate an independent marker of cellular aging, we further measured the protein level of endogenous CDK inhibitor p21Cip1, which is a transcriptional downstream target of p53. Increased expression of p21Cip1 is a well-known marker of replicative senescence 43 and has been demonstrated to be associated with stem-cell aging. 44 As Primary cultures were grown to confluence and monolayers were fixed and stained for ZO-1 (red) and beta-catenin (green) by the immunofluorescence.…”

Section: Epigenetic Modifications Of P53 Cause Mitochondrial Dysfunctmentioning

confidence: 99%

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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“…Bell and Sharpless [2] note that "inhibition of p21 seems to protect against the age-promoting effects of telomere dysfunction on stem cells, without an attendant rise in tumorigenesis. "…”

Section: Important Features For Aging Brain Datamentioning

confidence: 99%

“…2 We accessed the Gene Ontology (GO) [38] to find biological process information for this set of genes by using GO::TermFinder [3]. Examining the most frequent process label, five out of the 18 genes (27.8%) belonged to "glucose metabolic process" (LDHA, ALDOA, ENO1, PGAM1, and PKM2), with a very low p-value (2.06e-05).…”

Section: Important Features For Lymphoma Datamentioning

confidence: 99%

Understanding microarray data through applying competent program evolution

Looks

Goertzel²,

Coelho³

et al. 2007

Proceedings of the 9th Annual Conference on Genetic and Evolutionary Computation

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A number of researchers have used genetic programming (GP) to analyze gene expression microarray data; here it is asked whether the use of an alternate program evolution technique, MOSES (meta-optimizing semantic evolutionary search), can improve upon GP's results in this domain. Based on our results so far, the answer appears to be a resounding yes. We first consider standard supervised classification for two microarray datasets: one involving aging vs. young brains, and the other involving lymphoma types. On these datasets, MOSES is shown to learn classifiers with test accuracies comparable to those obtained by SVMs, and significantly superior to those of GP with a similar configuration (and even more superior to those of GP run under a more standard configuration). Furthermore, unlike SVMs, the classification rules produced by MOSES are still simple and comprehensible to humans -often strikingly simple. Finally, biological interpretation is presented regarding the "important genes" used most often in the ensemble of MOSES models learned; we show that many of the genes identified in this way reflect knowledge available in the literature, and others constitute plausible hypotheses.

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Telomeres, p21 and the cancer-aging hypothesis

Cited by 17 publications

References 14 publications

p21 Expression in Colon Cancer and Modifying Effects of Patient Age and Body Mass Index on Prognosis

p21 Expression in Colon Cancer and Modifying Effects of Patient Age and Body Mass Index on Prognosis

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

Understanding microarray data through applying competent program evolution

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