p53 in the CNS: Perspectives on Development, Stem Cells, and Cancer

Mendrysa, Susan M.; Ghassemifar, Sara; Malek, Reem

doi:10.1177/1947601911409736

Cited by 60 publications

(58 citation statements)

References 157 publications

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“…The specificity of the isoform-specific antibodies in immunofluorescence staining was confirmed using a p53-null cell line H358 with a Δ133p53, full-length p53, or p53β expression vector (Supplementary Figures S1A and B). As astrocytes were reported to be a major cell type showing p53 immunoreactivity in non-neoplastic human brain tissues, 32,33 we investigated whether the p53 isoforms would also be expressed in astrocytes and performed co-staining with astrocyte-specific marker glial fibrillary acidic protein (GFAP) (Figure 1a and Supplementary Figure S1C). Both p53β and Δ133p53 signals were detected in GFAP-positive cells and localized within 4 0 ,6-diamidino-2-phenylindole (DAPI)-positive nuclei ( Figure 1a and Supplementary Figure S1C, arrows).…”

Section: Resultsmentioning

confidence: 99%

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

et al. 2016

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Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

et al. 2016

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“…As p53 has also been shown to regulate reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), these findings argue in support of the idea that one of the roles of p53 is to tightly regulate homeostatic adult tissues. Similarly, p53 has been implicated in brain development (Liu et al 2007;Terzian et al 2007;Malek et al 2011;Mendrysa et al 2011). Although originally described as developmentally normal, Trp53 À/À mice were later shown to have development defects, including impaired maternal reproduction (Hu et al 2007), aberrant mesenchymal differentiation programs (Molchadsky et al 2008), and exencephaly (Armstrong et al 1995;Sah et al 1995).…”

Section: Discussionmentioning

confidence: 99%

The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo

et al. 2013

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The p53 tumor suppressor is a transcription factor that mediates varied cellular responses. The C terminus of p53 is subjected to multiple and diverse post-translational modifications. An attractive hypothesis is that differing sets of combinatorial modifications therein determine distinct cellular outcomes. To address this in vivo, a Trp53ΔCTD/ΔCTD mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53ΔCTD/ΔCTD mice die within 2 wk post-partum with hematopoietic failure and impaired cerebellar development. Intriguingly, the C terminus acts via three distinct mechanisms to control p53-dependent gene expression depending on the tissue. First, in the bone marrow and thymus, the C terminus dampens p53 activity. Increased senescence in the Trp53ΔCTD/ΔCTD bone marrow is accompanied by up-regulation of Cdkn1 (p21). In the thymus, the C-terminal domain negatively regulates p53-dependent gene expression by inhibiting promoter occupancy. Here, the hyperactive p53ΔCTD induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p53ΔCTD has wild-type DNA binding but impaired gene expression. Thus, the C terminus of p53 is needed in liver cells at a step subsequent to DNA binding. Finally, in the spleen, the C terminus controls p53 protein levels, with the overexpressed p53ΔCTD showing hyperactivity for gene expression. Thus, the C terminus of p53 regulates gene expression via multiple mechanisms depending on the tissue and target, and this leads to specific phenotypic effects in vivo.

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“…110 Stem cell regulation in the central nervous system and neurodegenerative diseases have been suggested to involve p53 and p73. 111,112 There may well be a price to pay for the diverse roles of p53 in stem cells. Several experiments suggest that too active a p53 response can deplete stem cells, in particular in bone marrow stem cells.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

The Regulation of Multiple p53 Stress Responses is Mediated through MDM2

2012

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The MDM2 oncogene is a key negative regulator of the p53 tumor suppressor protein. MDM2 and p53 form an autoregulatory feedback loop to tightly control the proper cellular responses to various stress signals in order to prevent mutations and tumor formation. The levels and function of the MDM2 protein, an E3 ubiquitin ligase, are regulated by a wide variety of extracellular and intracellular stress signals through distinct signaling pathways and mechanisms. These signals regulate the E3 ubiquitin ligase activity of MDM2, the ability of MDM2 to interact with p53 and a number of other proteins, and the cellular localization of MDM2, which in turn impact significantly upon p53 function. This review provides an overview of the regulation of MDM2 activities by the signals and factors that regulate the MDM2 protein, including genotoxic stress signals, oncogenic activation, cell cycle transition, ribosomal stress, chronic stress, neurohormones, and microRNAs. Disruption of the proper regulation of the MDM2-p53 negative feedback loop impacts significantly upon the frequency of tumorigenesis in a host. A better understanding of the complex regulation of MDM2 and its impact upon p53 function in cells under different conditions will help to develop novel and more effective strategies for cancer therapy and prevention.

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p53 in the CNS: Perspectives on Development, Stem Cells, and Cancer

Cited by 60 publications

References 157 publications

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo

The Regulation of Multiple p53 Stress Responses is Mediated through MDM2

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