Review Article
p53 at the crossroads between cancer and neurodegeneration

https://doi.org/10.1016/j.freeradbiomed.2012.02.034Get rights and content

Abstract

Aging, dementia, and cancer share a critical set of altered cellular functions in response to DNA damage, genotoxic stress, and other insults. Recent data suggest that the molecular machinery involved in maintaining neural function in neurodegenerative disease may be shared with oncogenic pathways. Cancer and neurodegenerative diseases may be influenced by common signaling pathways regulating the balance of cell survival versus death, a decision often governed by checkpoint proteins. This paper focuses on one such protein, p53, which represents one of the most extensively studied proteins because of its role in cancer prevention and which, furthermore, has been recently shown to be involved in aging and Alzheimer disease (AD). The contribution of a conformational change in p53 to aging and neurodegenerative processes has yet to be elucidated. In this review we discuss the multiple functions of p53 and how these correlate between cancer and neurodegeneration, focusing on various factors that may have a role in regulating p53 activity. The observation that aging and AD interfere with proteins controlling duplication and cell cycle may lead to the speculation that, in senescent neurons, aberrations in proteins generally dealing with cell cycle control and apoptosis could affect neuronal plasticity and functioning rather than cell duplication.

Graphical abstract

Highlights

► Multiple functions of p53 correlate between cancer and neurodegeneration. ► p53 maintains a delicate balance between cancer-suppressive and age-promoting functions. ► A conformational mutant p53 in cancer and aging is discussed. ► p53 is a transcription factor critical to decisions about cell fate.

Introduction

Cancer and neurodegenerative disorders are common age-related conditions. Cancer arises from a sequence of genetic and/or epigenetic events that regulate cellular differentiation and proliferation [1], [2], [3]. DNA methylation, histone acetylation, and other epigenetic modifications play roles in the activation and suppression of cancer genes and recent evidence suggests that defects in these events are linked to the progression of neurodegenerative disorders [2]. As far as changes in DNA methylation, the most studied aspect of epigenetic events, are concerned, a global hypomethylation of DNA has been found in various human cancers when samples were compared to healthy tissue counterparts [4]. Also, in Alzheimer disease (AD), the promoter region of the amyloid precursor protein (APP) gene, the precursor of β-amyloid (Aβ) peptide, has been shown to be hypomethylated with age [5], [6]. The gene for neprilysin, the major Aβ-degrading enzyme in the brain [7], is hypermethylated in cerebral endothelial cells after treatment with high concentrations of Aβ [8]. Furthermore, two recently identified genes, S100A2 and SORBS3, that have been implicated in memory storage in the central nervous system showed significantly different levels of DNA methylation in AD and control cases [9].

Recent data from the literature further support the concept that one or more common molecular mechanisms may be involved in the development of both neurodegenerative diseases and many cancers [10], [11], [12]. In particular, we focused on the relationship existing between cancer and AD. Because cancer is a disorder characterized by uncontrolled cell growth, whereas AD, as well as other neurodegenerative diseases, is denoted by atrophy and neuronal death, common signaling pathways regulating cell death and survival have been suggested to influence the development of these conditions. Epidemiological data from the literature suggest an inverse correlation between cancer and AD. In particular, older adults with prevalent clinical AD have been reported to develop incident cancer with slower growth rates compared to older adults without dementia and that individuals without dementia with a cancer history may be less prone to develop clinical AD [13], [14]. On the other hand, in the vast majority of studies, cancer seems to be a prevalent comorbidity for patients with AD [15]. Furthermore, in a postmortem histopathological study, unreported signs of AD were found in 42% of patients diagnosed with brain cancer and in 48% of cases without glioblastoma, suggesting that coexistence of both diseases is often uninvestigated and consequently underreported in the clinical literature [16]. Alternatively, it is possible that brain cancers give rise to a brain milieu favoring amyloid deposition and neurofibrillary tangle formation.

Taking into account that cancer and AD share common signaling pathways directing cell fate toward either death or survival, the identification of the putative common mechanisms may be useful to better understand these two disorders as well as to develop more appropriate therapeutic strategies. It is noteworthy that the balance of cell survival versus death is at least in part regulated by a fine timing of checkpoint proteins, the preservation of DNA integrity, and correct repair [17], [18]. Among cell cycle proteins, p53 is particularly significant because of its role in stopping cells in G0/G1 and G2/M phases, thus either allowing DNA repair or activating a programmed cell death. p53 dysfunctional activity is involved in cancer progression, but also in aging and AD. In mammals, loss of p53 increases carcinogenesis, whereas specific gain-of-function alleles reduce the incidence of cancer but accelerate aging, suggesting a trade-off between cancer surveillance and stem cell maintenance [19]. Yang and co-workers demonstrated the existence of aberrant neurons in AD brain by showing that neurodegeneration is correlated with neurons reentering a lethal cell cycle [20], which suggests that dysfunctional p53 in nondividing cells may play a role in aberrant cell cycle progression.

In this review we discuss the multiple functions of p53 and how these correlate between cancer and neurodegeneration, focusing on various factors that may have a role in the regulation of p53 activity.

Section snippets

p53: a transcription factor critical to decisions about cell fate

p53 is a very short-lived protein that exists in a wild-type latent conformation and is activated in response to a great variety of stresses that can damage the integrity of the cell genome [21], [22]. Among these, DNA damage, hypoxia and activation of oncogenes are potent activators of p53 protein. Stabilization and induction of p53 transcriptional activity depend mainly on posttranslational modifications together with protein/protein interactions [23]. The regulation of p53 activity is

p53 in cancer: mutations as more than a loss of function

The predominant mode of p53 inactivation in about 50% of human primary cancers is by point mutation rather than by deletion or truncation [38]. Mutational analysis of the p53 gene, conducted using the International Agency for Research Cancer database, revealed that almost all hot-spot mutations are located within the DNA-binding domain of the protein. These mutations may have structural consequences: DNA contact is lost, conformation of the DNA-binding domain is locally perturbed, or the entire

Mutation-independent conformationally altered p53 in cancer development: the role of oxidative stress

Stabilization and overexpression of p53 have been often considered markers of mutant p53. Mutant p53 stabilization depends on impaired ubiquitination due to the loss of wild-type (wt) p53 structure. The molecular basis of a prolonged half-life of mutant p53 might partially depend on the inefficient degradation exerted by the E3 ubiquitin ligase MDM-2, whose gene is a direct transcriptional target of wt p53 [see for review 51]. However, the corresponding mutant p53 accumulation of protein is not

p53: a delicate balance between cancer-suppressive and age-promoting functions

Recent observations suggest that p53 may play a central role in aging and in neurodegenerative disorders [68], [69], [70], [71], [72], [73]. In this review we mainly focused on the p53 role in AD [74], yet we must not forget that this protein has been related to other neurodegenerative diseases [75], [76]. Even if it is still a matter of controversy whether organism aging is due to a programmed process or is the consequence of failed mechanisms involved in regeneration or repair tissues, p53

p53 and Alzheimer disease: not only a killer

Evidence of the pivotal function of p53 in neuronal death is provided by data from both in vitro and in vivo models. A strong correlation between p53 expression and excitotoxic neuronal death induced by glutamate, kainic acid, and N-methyl-d-aspartate has been established [86], [87]. Also in 1998 our group demonstrated that glutamate- and kainate-induced neuronal death was p53-dependent [88]. Furthermore, increased p53 immunoreactivity associated with neuronal death was observed in models of

Conformational mutant p53 in aging and Alzheimer disease

Focusing on the study of p53-induced signaling responses in peripheral cells of AD patients and age-matched controls, the lack of p53 functional activity has been observed in AD fibroblasts after cytotoxic insults. Such impairment was demonstrated to be due to conformational changes in p53 tertiary structure, selectively occurring in AD cells [63], [104]. Furthermore, p53 has been studied in blood cells of aged controls and demented patients, with data demonstrating an age-related increase in

Conclusion

The type of cell death involved in AD is still controversial, but it is clear that there is progressive atrophy of the brain due to cell and synaptic loss. The average time course of AD is 10 years from first symptoms to death. If we consider that a typical apoptotic process takes roughly 12 h and that few neurons (fewer than 1/10,000 at any given time) exhibit signs of apoptosis [119], we could speculate that neuronal death is not the result of a single acute insult. Hence, like cancer, AD may

Acknowledgment

This work was supported by grants from the UNIPV-Regione Lombardia (to C.L.).

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