Expression of the polyalanine expansion mutant of nuclear poly(A)‐binding protein induces apoptosis via the p53 pathway

Bhattacharjee, Rumpa Biswas; Zannat, Thangima; Bag, Jnanankur

doi:10.1042/cbi20110348

Cited by 12 publications

(11 citation statements)

References 38 publications

(82 reference statements)

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“…To detect normal, apoptotic and necrotic cells, acridine orange/ethidium bromide (AO/EB) double staining was used as previously described [26]. Cells were classified as normal, apoptotic and necrotic as described by Baskic et al, 2006 [27].…”

Section: Methodsmentioning

confidence: 99%

Depletion of Nuclear Poly(A) Binding Protein PABPN1 Produces a Compensatory Response by Cytoplasmic PABP4 and PABP5 in Cultured Human Cells

Bhattacharjee

Bag

2012

PLoS ONE

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BackgroundIn vertebrates, poly(A) binding protein (PABP) is known to exist in five different isoforms. PABPs are primarily cytosolic with the exception of the nuclear PABP (PABPN1), which is located in the nucleus. Within the nucleus, PABPN1 is believed to bind to the poly(A) tail of nascent mRNA and along with cleavage and polyadenylation specificity factor (CPSF) define the length of the newly synthesized poly(A) tail.Methodology/Principal FindingsThe cellular role of PABP1 has been extensively studied over the years; however, the function of other PABPs remains poorly defined. In order to understand the role of PABPN1 in cellular mRNA metabolism and it’s interrelation with other PABPs, we depleted PABPN1 using RNAi in HeLa and HEK293 cells. Our results show that PABPN1 depletion did not have any effect on the poly(A) tail length, nuclear export of mRNA, mRNA translation, and transcription. Rather, PABPN1 depletion resulted in a compensatory response as observed by increased level of PABP5 and nuclear accumulation of PABP4. In addition, PABP4 was associated with the poly(A) tract of pre-mRNA and CPSF in PABPN1 depleted cells. Nevertheless, PABPN1 depletion significantly affected cell survival as evidenced by an increase in apoptosis markers: phosphorylated p53 and PUMA and as judged by the expression of ER stress marker GRP78.ConclusionOur results suggest that although function of PABPN1 may be compensated by nuclear translocation of PABP4 and perhaps by increase in the cytoplasmic abundance of PABP5, these were not sufficient to prevent apoptosis of cells. Thus PABPN1 may have a novel anti apoptotic role in mammalian cells.

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Section: Methodsmentioning

confidence: 99%

Depletion of Nuclear Poly(A) Binding Protein PABPN1 Produces a Compensatory Response by Cytoplasmic PABP4 and PABP5 in Cultured Human Cells

Bhattacharjee

Bag

2012

PLoS ONE

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“…However, mitochondrial dysfunction, the formation of the mitochondrial permeability transition pore, Cyt. c release, and the translocation of pro-apoptotic BAX to mitochondria have been observed in mammalian polyA models (Toriumi et al, 2008, 2009; Bhattacharjee et al, 2012). Therefore, it might be a fruitful approach to dissect the role of mitochondria in polyA-triggered cytotoxicity in yeast.…”

Section: Neurotoxic Yeast Modelsmentioning

confidence: 98%

Mitochondrion-mediated cell death: dissecting yeast apoptosis for a better understanding of neurodegeneration

Braun¹

2012

Front. Oncol.

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Mitochondrial damage and dysfunction are common hallmarks for neurodegenerative disorders, including Alzheimer, Parkinson, Huntington diseases, and the motor neuron disorder amyotrophic lateral sclerosis. Damaged mitochondria pivotally contribute to neurotoxicity and neuronal cell death in these disorders, e.g., due to their inability to provide the high energy requirements for neurons, their generation of reactive oxygen species (ROS), and their induction of mitochondrion-mediated cell death pathways. Therefore, in-depth analyses of the underlying molecular pathways, including cellular mechanisms controlling the maintenance of mitochondrial function, is a prerequisite for a better understanding of neurodegenerative disorders. The yeast Saccharomyces cerevisiae is an established model for deciphering mitochondrial quality control mechanisms and the distinct mitochondrial roles during apoptosis and programmed cell death. Cell death upon expression of various human neurotoxic proteins has been characterized in yeast, revealing neurotoxic protein-specific differences. This review summarizes how mitochondria are affected in these neurotoxic yeast models, and how they are involved in the execution and prevention of cell death. I will discuss to which extent this mimics the situation in other neurotoxic model systems, and how this may contribute to a better understanding of the mitochondrial roles in the human disorders.

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“…Although apoptosis has not been reported in muscles of OPMD patients, markers of apoptosis are significantly increased in some of these cell culture studies . Experiments performed in HeLa and human embryonic kidney (HEK 293) cells identify the p53 pathway as a key mediator of apoptosis resulting from expression of alanine‐expanded PABPN1 , which is similar to the mechanism of neuronal apoptosis linked to some polyglutamine expansion diseases . Expressing both wild‐type and alanine‐expanded PABPN1 simultaneously in monkey fibroblast cells (COS) decreased the expression of apoptotic markers compared with cells expressing alanine‐expanded PABPN1 alone.…”

Section: Approaches Used To Study the Effects Of Mutant Pabpn1mentioning

confidence: 99%

PABPN1: molecular function and muscle disease

et al. 2013

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The polyadenosine RNA binding protein, polyadenylate-binding nuclear protein 1 (PABPN1), plays key roles in post-transcriptional processing of RNA. Although PABPN1 is ubiquitously expressed and presumably contributes to control of gene expression in all tissues, mutation of the PABPN1 gene causes the disease Oculopharyngeal Muscular Dystrophy (OPMD), in which a limited set of skeletal muscles are effected. A major goal in the field of OPMD research is to understand why mutation of a ubiquitously expressed gene leads to a muscle-specific disease. PABPN1 plays a well-documented role in controlling the poly(A) tail length of RNA transcripts but new functions are emerging through studies that exploit a variety of unbiased screens as well as model organisms. This review addresses: (1) the molecular function of PABPN1 incorporating recent findings that reveal novel cellular functions for PABPN1 and (2) the approaches that are being used to understand the molecular defects that stem from expression of mutant PABPN1. The long-term goal in this field of research is to understand the key molecular functions of PABPN1 in muscle as well as the mechanisms that underlie the pathological consequences of mutant PABPN1. Armed with this information, researchers can seek to develop therapeutic approaches to enhance the quality of life for patients afflicted with OPMD.

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Expression of the polyalanine expansion mutant of nuclear poly(A)‐binding protein induces apoptosis via the p53 pathway

Cited by 12 publications

References 38 publications

Depletion of Nuclear Poly(A) Binding Protein PABPN1 Produces a Compensatory Response by Cytoplasmic PABP4 and PABP5 in Cultured Human Cells

Depletion of Nuclear Poly(A) Binding Protein PABPN1 Produces a Compensatory Response by Cytoplasmic PABP4 and PABP5 in Cultured Human Cells

Mitochondrion-mediated cell death: dissecting yeast apoptosis for a better understanding of neurodegeneration

PABPN1: molecular function and muscle disease

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