Alteration of Intracellular Structure and Function of Glyceraldehyde-3-Phosphate Dehydrogenase: A Common Phenotype of Neurodegenerative Disorders?

Mazzola, Jennifer L.; Sirover, Michael A.

doi:10.1016/s0161-813x(02)00062-1

Cited by 79 publications

(53 citation statements)

References 59 publications

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“…Furthermore the treated cells showed a marked increase of the expression of both glyceraldehyde 3-phosphate dehydrogenase (Gapdh) and enolase. These two proteins are involved in energy metabolism and Gapdh has also been shown to bind the β-amyloid precursor protein [18] and to be involved in transcriptional regulation of cell-cycle [19]. Finally, we observed an increase in the expression level of actin as previously shown in cell exposed to the intracellular domain of the β-amyloid precursor protein [20].…”

Section: Biochimica Et Biophysica Acta 1794 (2009) 1243-1250supporting

confidence: 83%

“…Furthermore, increased expression and nuclear translocation of Gapdh have recently been reported to participate to the apoptotic pathway in different cell types [44][45][46][47]. Finally, Gapdh has also been reported to bind to a variety of proteins involved in neuronal diseases, including the amyloid precursor protein and huntingtin [18]. The increased levels of actin expression in cells exposed to prefibrillar HypF-N aggregates are similar to the effects previously reported by Muller et al; these authors found up-regulation of the actin gene expression in cells harbouring the cytoplasmic domain of the amyloid precursor protein [20].…”

Section: Discussionmentioning

confidence: 99%

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Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

Magherini

Pieri

Guidi

et al. 2009

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Several human diseases are associated with the deposition of stable ordered protein aggregates known as amyloid fibrils. In addition, a large wealth of data shows that proteins not involved in amyloidoses, are able to form, in vitro, amyloid-like prefibrillar and fibrillar assemblies indistinguishable from those grown from proteins associated with disease. Previous studies showed that early prefibrillar aggregates of the N-terminal domain of the prokaryotic hydrogenase maturation factor HypF (HypF-N) are cytotoxic, inducing early mitochondria membrane depolarization, activation of caspase 9 and eventually cell death. To gain knowledge on the molecular basis of HypF-N aggregate cytotoxicity, we performed a differential proteomic analysis of NIH-3T3 cells exposed to HypF-N prefibrillar aggregates in comparison with control cells. Two-dimensional gel electrophoresis followed by protein identification by MALDI-TOF MS, allowed us to identify 21 proteins differentially expressed. The changes of the expression level of proteins involved in stress response (Hsp60 and 78 kDa glucose-regulated protein) and in signal transduction (Focal adhesion kinase1) appear particularly interesting as possible determinants of the cell fate. The levels of some of the differently expressed proteins were modified also in similar studies carried out on cells exposed to Aβ or α-synuclein aggregates, supporting the existence of shared features of amyloid cytotoxicity.

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Section: Biochimica Et Biophysica Acta 1794 (2009) 1243-1250supporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

Magherini

Pieri

Guidi

et al. 2009

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…We previously demonstrated that GAPDH is a member of a protein complex that recognizes modified DNA (15), and this complex was destroyed by an anti-GAPDH monoclonal antibody (15). Although protein-protein interacting domains within GAPDH, other than those involved in oligomerization, have not been defined, GAPDH is known to form a variety of protein-protein complexes (15,22). Selective binding of GAPDH to ␤-amyloid precursor protein, huntingtin, ␣-synuclein, parkin, atrophin, ataxin-1, and androgen receptor indicate a potential role of GAPDH in neurodegenerative diseases associated with expansion of CAG repeats (4,22).…”

Section: Discussionmentioning

confidence: 99%

“…Although protein-protein interacting domains within GAPDH, other than those involved in oligomerization, have not been defined, GAPDH is known to form a variety of protein-protein complexes (15,22). Selective binding of GAPDH to ␤-amyloid precursor protein, huntingtin, ␣-synuclein, parkin, atrophin, ataxin-1, and androgen receptor indicate a potential role of GAPDH in neurodegenerative diseases associated with expansion of CAG repeats (4,22). This proclivity to form multiprotein complexes led us to speculate that its partner proteins may play an important role in determining multiple biological functions of GAPDH within the cell.…”

Section: Discussionmentioning

confidence: 99%

A Novel CRM1-mediated Nuclear Export Signal Governs Nuclear Accumulation of Glyceraldehyde-3-phosphate Dehydrogenase following Genotoxic Stress

Brown

Krynetski

Krynetskaia

et al. 2004

Journal of Biological Chemistry

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein with glycolytic and nonglycolytic functions, including pro-apoptotic activity. GAPDH accumulates in the nucleus after cells are treated with genotoxic drugs, and it is present in a protein complex that binds DNA modified by thioguanine incorporation. We identified a novel CRM1-dependent nuclear export signal (NES) comprising 13 amino acids (KKVVKQASEGPLK) in the C-terminal domain of GAPDH, truncation or mutation of which abrogated CRM1 binding and caused nuclear accumulation of GAPDH. Alanine scanning of the sequence encompassing the putative NES demonstrated at least two regions important for nuclear export. Site mutagenesis of Lys 259 did not affect oligomerization but impaired nuclear efflux of GAPDH, indicating that this amino acid residue is essential for proper functioning of this NES. This novel NES does not contain multiple leucine residues unlike other CRM1-interacting NES, is conserved in GAPDH from multiple species, and has sequence similarities to the export signal found in feline immunodeficiency virus Rev protein. Similar sequences (KKVV*7-13PLK) were found in two other human proteins, U5 small nuclear ribonucleoprotein, and transcription factor BT3.

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“…Two hypotheses may explain our results: GAPDH is undergoing posttranslational modifications and/or degradation in the normal tissue or GAPDH is modified and accumulates at detectable levels in the ccRCC tissue, whereas in the normal tissue it is present at undetectable levels. Previous works suggest that GAPDH is indeed target of modifications that can modulate its cellular level (12,13).…”

Section: Discussionmentioning

confidence: 99%

Differencial proteome of clear-cell renal cell carcinoma (ccRCC) tissues

et al. 2013

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Purpose: We attempted to detect, for the first time in a Brazilian cohort, differences in protein expression between clear-cell renal cell carcinoma (ccRCC) and their normal adjacent tissues, aiming to identify biomarkers and/or therapeutic target candidates for this disease. Material and Methods: Twenty-four ccRCC and adjacent normal tissues were collected after surgery and their protein extracts were quantified, pooled and separated by two--dimensional polyacrylamide gel electrophoresis (2DE), followed by statistical analysis of the stained gels. Spots of interest were excised from the gels, digested with trypsin and identified by MALDI-TOF-TOF mass spectrometry. Results: Twenty-six differential spots were detected between the two classes of tissues, among which twenty were identified by mass spectrometry and sixteen were found to be non-redundant. Eleven proteins were either underexpressed or undetected in the ccRCC extracts, such as prohibitin and peroxiredoxin-3, whereas five were found to be overexpressed or exclusively detected in the ccRCC extract, including αβ crystalin and heat shock protein 27. Conclusions: Several proteins were detected at differential levels when compared to normal adjacent tissues, and, moreover, many have been previously described by their relationship with RCC. Therefore, this work corroborates previous reports on the search for biomarkers for ccRCC, as well as it points out new candidates that may be validated in future studies.

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Alteration of Intracellular Structure and Function of Glyceraldehyde-3-Phosphate Dehydrogenase: A Common Phenotype of Neurodegenerative Disorders?

Cited by 79 publications

References 59 publications

Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

A Novel CRM1-mediated Nuclear Export Signal Governs Nuclear Accumulation of Glyceraldehyde-3-phosphate Dehydrogenase following Genotoxic Stress

Differencial proteome of clear-cell renal cell carcinoma (ccRCC) tissues

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