Review ArticleReview

Critical protein GAPDH and its regulatory mechanisms in cancer cells

Jin-Ying Zhang, Fan Zhang, Chao-Qun Hong, Armando E. Giuliano, Xiao-Jiang Cui, Guang-Ji Zhou, Guo-Jun Zhang and Yu-Kun Cui
Cancer Biology & Medicine March 2015, 12 (1) 10-22; DOI: https://doi.org/10.7497/j.issn.2095-3941.2014.0019

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and posttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 (HIF-1), p53, nitric oxide (NO), and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications (PTMs) occurring in GAPDH in cancer cells result in new activities unrelated to the original glycolytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described.

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Introduction

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme specifically catalyzing the reversible conversion of glyceraldehyde-3-phosphate (G-3-P) to 1,3-diphosphoglycerate. GAPDH participates in numerous cellular functions, in addition to glycolytic effects. For instance, GAPDH contributes to nuclear tRNA export, DNA replication and repair, endocytosis, exocytosis, cytoskeletal organization, iron metabolism, carcinogenesis, and cell death1,2.

Although GAPDH is widely used as an internal control, its expression status varies in different human cell lines3. Remarkably increased GAPDH levels are observed in many human cancer types and often correlated with reduced survival4,5. GAPDH is also considered as a pro-apoptotic agent1,6. Therefore, these deregulations of GAPDH in cancers indicate the inconsistent roles of this enzyme in cell fate determination1,5. However, these cancer-related mechanisms involved in GAPDH regulation remain unclear.

GAPDH is a homo tetramer containing four identical 37 kDa subunits. Localized in chromosome 12, human GAPDH gene transcribes single mRNA species, consequently producing a subunit that comprises a polypeptide chain of 335 amino acids7,8. GAPDH is regulated at a transcriptional level, and its functional diversity is largely affected by posttranslational modifications (PTMs) in different amino acid residues1. Moreover, many molecules not only regulate mRNA levels but also affect cancer-related functions (proliferation, tumor formation, chemoresistance, and so on) of GAPDH8. In this review, transcription-related events are described; the association of molecules with GAPDH is also discussed to determine mechanisms and pathways implicated in GAPDH regulation. Furthermore, diverse GAPDH-related PTMs, which influence the functions of this enzyme in cancer cells, are identified.

Factors affecting GAPDH gene expression and protein functions

Insulin

Early research on hepatoma cells has showed that insulin increases mRNA levels of GAPDH9. Further studies have revealed insulin response elements (IRE) in the upstream regulatory region of the GAPDH gene10. Among these elements, both IRE-A (−480 to −435) and IRE-B (−408 to −269) play important roles in GAPDH transcription. In a study on H35 hepatoma cells, IRE-A and IRE-B interact to enhance GAPDH transcription levels up to nearly 8-fold after insulin treatment is administered10. Furthermore, two insulin-sensitive DNA binding proteins (IBP) interact with these two elements10. These findings suggest that insulin increases GAPDH expression levels at a transcriptional level. In addition, this mechanism partially explains the overexpression of GAPDH in some cancer cells at mRNA and protein levels11–13.

Studies on colon cancer cells have shown that insulin causes drug resistance and decreases chemotherapy efficacy by the activation of PI3K/AKT pathway14,15. Insulin is involved in the activation of AKT, a serine/threonine kinase, which phosphorylates many downstream proteins, including GAPDH16. AKT can phosphorylate GAPDH and enhance its glycolytic activity16. Interestingly, GAPDH in cancer cells interacts with active AKT and inhibits dephosphorylation; as a result, Bcl-xl is overexpressed, thereby protecting cancer cells from caspase-independent cell death (CICD)17. In human hepatocellular carcinoma cells, colony formation in vitro and tumor formation in vivo are decreased as GAPDH glycolytic enzyme activity is significantly decreased and phosphorylated AKT (p-AKT) is reduced when GAPDH expression is suppressed by GAPDH antagonist 3-bromopyruvate (3-BrPA) or shRNA18. In addition to glycolysis, GAPDH suppression decreases p-AKT and participates in tumor formation and proliferation19. Likewise, GAPDH inhibition caused by antisense oligonucleotides in human cervical carcinoma affects cell proliferation and induces apoptosis20. In addition, GAPDH is a protein target of saframycin A to decrease cancer cell proliferation21. Insulin-induced regulatory mechanism of GAPDH is summarized in Figure 1.

Figure 1
Figure 1

Regulatory mechanisms of GAPDH by insulin and hypoxia. Insulin and hypoxia stimulate GAPDH gene expression and activate PI3K/AKT pathway. Active AKT phosphorylates GAPDH and induces drug resistance, proliferation, and tumor formation of cancer cells. Overexpressed GAPDH interacts with active AKT and sustains enzyme activity. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IBP, insulin-binding protein; IRE, insulin response elements; HRE, hypoxia response elements; HIF-1α, hypoxia inducible factor-1α.

Hypoxia inducible factor-1 (HIF-1)

In a study on endothelial cells, GAPDH gene expression is increased under hypoxia stress22. In another study, a hypoxia response element (HRE) is found in the GAPDH gene; this HRE is a 19-nucleotide sequence (−130 to −112) containing a transcription factor HIF-1 binding site23. The mRNA level of GAPDH is increased by approximately 75% under hypoxic condition; GAPDH overexpression is correlated with the upregulation of HIF-1α protein levels24. Increased HIF-1α protein levels and expression of the corresponding downstream genes encoding glycolytic enzymes are associated with mutations that activate oncogenes or inactivate tumor suppression genes25.

Hypoxia is a condition characterized by a decrease in oxygen level and pathophysiological condition in solid tumors26. Hypoxia signaling is involved in aggressive tumor behaviors27. In a study on lung cancer cells, hypoxia activates the PI3K/AKT pathway and induces resistance to drug-mediated apoptosis28. In prostate and gastric cancer cells, AKT contributes to HIF-1α expression and accumulation29,30. Therefore, p-AKT enhances aerobic glycolysis rate in cancer cells because p-AKT can promote the expression of glycolytic enzymes, including GAPDH, via HIF-131. Furthermore, aerobic glycolysis is the main metabolic pathway of cancer cells related to cell proliferation32. As an important glycolytic enzyme, GAPDH participates in cancer cell proliferation5.

Insulin enhances HIF-1α at mRNA and protein levels in adipose tissue33. In a further study on pancreatic cancer, insulin stimulates HIF-1α expression under hypoxic condition; in turn, insulin requires HIF-1α to promote glycolysis and cell proliferation34. With HIF-1α, insulin regulates glucokinase gene expression via the PI3K/AKT pathway35. Figure 1 shows the regulatory mechanisms of GAPDH by hypoxia and insulin.

p53

mRNA and protein levels of GAPDH are upregulated by p5336. In a study on cytosine arabinoside-induced apoptosis, mRNA and protein levels of GAPDH are increased after p53 is overexpressed; GAPDH regulation is effectively suppressed by p53 antisense oligonucleotide. Moreover, high-efficiency transfection of p53 gene into PC12 cells results in a remarkable overexpression of not only p53 but also GAPDH36. These results suggest that GAPDH overexpression is an event occurring downstream of p53; however, the specific mechanism remains unclear36.

As a tumor suppressor, p53 induces cell death after DNA is damaged37. p53 is also a transcription factor that directly binds to the promoter region of SIAH1 gene; as a result, SIAH1 expression is increased38. SIAH1, seven in absentia homolog 1, is an E3 ubiquitin ligase, which moves to the nucleus and facilitates the degradation of nuclear proteins; as a consequence, apoptosis is induced39. Hara et al.40,41 have revealed that GAPDH binds to SIAH1; once bound, GAPDH translocates to the nucleus and stabilizes SIAH1 activity; the bound GAPDH then participates in apoptosis. Thus, p53 can upregulate the mRNA transcription of GAPDH and stimulate its participation in cell death via the SIAH1-GAPDH cascade1. In the absence of poly A binding protein, nuclear GAPDH enhances acetylation and serine 46 phosphorylation of p53, as well as its pro-apoptotic functions42. Likewise, a complex with p53 is formed, and p53 expression and phosphorylation are enhanced when GAPDH translocates to the nucleus in SIAH1-dependent manner43. If the p53/GAPDH complex is disrupted, cell death and GAPDH-mediated p53 upregulation and phosphorylation are possibly blocked43. Therefore, an auto-amplifying loop may exist in p53/GAPDH-induced apoptosis. Nevertheless, this mechanism leading to apoptosis can be prevented. In a study on ovarian cancer cells, AKT2 inhibits GAPDH nuclear translocation and suppresses GAPDH-induced apoptosis44. In breast cancer, GAPDH nuclear accumulation is also prevented via AKT signaling45.

Acetylation and phosphorylation of p53 are enhanced when GAPDH is located in the nucleus; p53 then translocates to the mitochondria to initiate apoptosis42. Furthermore, p53 in the mitochondria directly induces a second mitochondrion-derived caspase release, which is required for apoptosis46. Although AKT attenuates p53 accumulation in the mitochondria and caspase release, AKT inhibits caspase-dependent cell death46,47. Tarze et al.48 have reported that GAPDH also accumulates in the mitochondria and causes pro-apoptotic mitochondrial membrane permeabilization, which triggers intrinsic apoptotic pathway. In isolated mitochondria, GAPDH becomes imported, interacts with a voltage-dependent anion channel, and mediates permeability transition; as a result, the release of two pro-apoptotic proteins, namely, cytochrome C and apoptosis-inducing factor, is induced48. However, the regulatory mechanisms of GAPDH translocation in the mitochondria remain unclear. During apoptosis, the rapid loss of mitochondrial function is dependent on the subsequent activation of caspases promoted by the release of cytochrome C, not on mitochondrial outer membrane permeabilization (MOMP)49. Once caspase is inhibited, MOMP eventually leads to CICD50. Intriguingly, GAPDH protects cells from CICD, and this protection is dependent on an increase in glycolysis rate, nuclear translocation, and enhanced autophagy49,51. Furthermore, overexpressed GAPDH binds to active AKT and inhibits AKT dephosphorylation. Stabilized by GAPDH, active AKT induces phosphorylation but prevents nuclear localization of FoxO; thus, Bcl-6 levels are downregulated. Bcl-6 is a transcriptional inhibitor; a decrease in this inhibitor leads to Bcl-xL overexpression. This GAPDH-dependent increase in Bcl-xL protects the mitochondria from permeabilization; as a consequence, cells evade CICD17. In the nucleus, GAPDH enhances p53-mediated mitochondrion cell death; AKT inhibits GAPDH nuclear translocation and p53 mitochondrial translocation42,46. In the cytoplasm, overexpressed GAPDH protects tumor cells from CICD via AKT signaling pathway17 (Figure 2).

Figure 2
Figure 2

Regulatory mechanisms of GAPDH by p53 and NO. p53 and NO enhance GAPDH gene expression via unclear pathways. GAPDH enhances p53 accumulation and amplifies regulatory effect. p53 also stimulates gene expression and increases protein levels of SIAH1. Cytoplasmic GAPDH binds to SIAH1, and the bound GAPDH transports to the nucleus. SIAH1 facilitates the degradation of target proteins and consequently induces apoptosis. In this procedure, GAPDH stabilizes SIAH1 activity. NO enhances the binding ability of GAPDH to SIAH1. p53 and GAPDH stimulate mitochondrion-mediated apoptosis. Interestingly, AKT inhibits these two apoptotic pathways. NO strongly decreases phosphorylated AKT levels in cancer cells. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NO, nitric oxide.

p53-induced apoptosis can be inhibited by insulin. In the kidney, high glucose induces early nephron apoptosis partially mediated by p53; conversely, insulin treatment blocks this process52. In human cervical carcinoma cells, insulin inhibits p53 accumulation53. p53 is also activated by hypoxia; moreover, p53 interacts with HIF-1α and induces ubiquitin-mediated proteosomal degradation of HIF-1α, but p53 expression is not correlated with HIF-1α expression; HIF-1α might be regulated by p53 and other factors54,55. In a study on colon cancer cells, HIF-1 inhibits the activation of intrinsic cell death pathway when p53 is deficient56. However, the combined effects of insulin, HIF-1, and p53 on GAPDH regulation remain unclear and thus warrant further studies.

NO

In murine microvascular endothelial cells, mRNA levels of GAPDH are strongly increased after these cells are treated with TNF-α and IFN-γ; upregulation is blocked by nitric oxide (NO) synthesis inhibitors57. Therefore, endogenous NO can induce an increase in the mRNA expression of GAPDH57. Furthermore, NO modifies GAPDH (described later) and induces the translocation of GAPDH from the cytoplasm to the nucleus by enhancing the binding to SIAH1; the bound GAPDH then participates in apoptosis58,59. In gastric cancer cells, NO strongly decreases the levels of active AKT and suppresses cancer cell growth60. In ovarian cancer cells, NO donors inhibit AKT phosphorylation, prevent uncontrolled proliferation and metastasis of cancer cells, and induce cell death (Figure 2)61.

NO is produced and released from NO donors and NO synthase (NOS). NO donors increase p53 levels; NOS is transcriptionally downregulated by p53 and NOS activity is enhanced by insulin62,63. In solid tumors, NO inhibits hypoxia-induced chemoresistance64. Likewise, the combined effects of insulin, HIF-1, p53, and NO on GAPDH regulation remain obscure.

Acetylated histone

Despite these factors, a specific molecule can downregulate gene expression and affect intracellular functions of GAPDH. In a research on glioma cells, the histone deacetylase (HDAC) inhibitor 4-phenylbutyrate (4-PB), which enhances acetylated histone, suppresses the mRNA level of GAPDH and induces apoptosis65. Valproic acid (VPA), another HDAC inhibitor, decreases GAPDH accumulation in the nucleus and consequently inhibits apoptosis66. These data confirm the inconsistent effects of HDAC inhibitors on cell fate determination; such inconsistencies are probably attributed to other cellular functions of these compounds67. For instance, 4-PB is described as an endoplasmic reticulum stress inhibitor, whereas VPA can induce mitochondrial damage and oxidative stress68,69. These processes may lead to oxidative modifications of GAPDH. Interestingly, GAPDH promotes histone acetylation. In the nucleus, S-nitrosylated GAPDH transnitrosylates HDAC. Once nitrosylated, HDAC dissociates from chromatin; as a result, histone acetylation is enhanced70,71. Furthermore, GAPDH can promote histone transcription. As a part of the OCA-S complex (a multicomponent Oct-1 co-activator), GAPDH binds to Oct-1 directly. In the S phase, GAPDH becomes recruited to histone-2B promoter and enhances the transcription of this promoter72. This result confirms the association of GAPDH with cell cycle regulation. Furthermore, overexpressed GAPDH is associated with cell cycle genes related to malignant stage and unfavorable prognosis73. Likewise, AKT participates in this regulatory mechanism of GAPDH via acetylated histone because AKT can stimulate histone acetylation74.

The regulatory mechanisms of these factors in GAPDH gene expression and protein functions are summarized in Table 1.

View this table:
Table 1

Regulatory mechanisms of gene expression and protein function of GAPDH

PTMs of GAPDH

Possible mechanisms and pathways involved in GAPDH regulation have been discussed. GAPDH can also be regulated by other mechanisms. PTMs play important roles in regulating diverse GAPDH functions in cancer cells1,75.

GAPDH phosphorylation plays inconsistent roles in cancer cells

In rat cardiac muscle, phosphorylated-GAPDH (p-GAPDH) is increased after AKT is activated16. In human ovarian cancer, AKT2 phosphorylates GAPDH at threonine 237 and prevents the nuclear translocation of GAPDH; as a result, the participation of GAPDH in apoptosis is impeded44. This result suggests that AKT-induced phosphorylation of GAPDH plays an important role in blocking cancer cell apoptosis.

In addition to AKT/PKB, protein kinase C (PKC) phosphorylates GAPDH. Tisdale et al. reported that PKCι/λ also phosphorylates GAPDH76; in this manner, GAPDH interacts with PKCι/λ and Rab2. Binding is implicated in microtubule dynamics in early secretory pathway77,78. Furthermore, PKCι/λ-mediated GAPDH phosphorylation is inhibited by Rab2-PKCι/λ interaction79. The interaction of GAPDH-PKCι/λ-Rab2 also plays an essential role in membrane recruitment and fusion80. GAPDH is Src-phosphorylated at tyrosine and is necessary to bind to PKCι/λ in early secretory pathway81. In cervical cancer, GAPDH interacts with Rab2 and participates in membrane recruitment82. Despite the presence of GAPDH-PKCι/λ-Rab2 in cancer cells, functions of the complex remain unclear. In addition, PKCδ can phosphorylate GAPDH in the mitochondria83. During ischemia and reperfusion or reoxygenation (I/R)-induced injury, GAPDH accumulates in the mitochondria, promotes the formation of lysosomal-like structures, and induces the uptake of the mitochondria into these structures83. However, GAPDH-driven mitophagy is possibly inhibited when PKCδ translocates to the mitochondria and phosphorylates GAPDH at threonine 24683. In HeLa cells, GAPDH enhances mitophagy and induces cancer cell survival49. PKCδ-induced phosphorylation of GAPDH may be inhibited in cancer cells to induce survival.

S-nitrosylation of GAPDH facilitates apoptosis

GAPDH is S-nitrosylated by NO and consequently binds to SIAH1, which translocates GAPDH to the nucleus and induces cell death41. NO also induces S-nitrosylation of GAPDH at Cys15284. In HeLa cells, G-3-P partially protects GAPDH from S-nitrosylation; as a consequence, GAPDH-SIAH1 complex levels are decreased and cell survival is maintained85. In the cytoplasm, a novel protein interactor of GAPDH named GOSPEL (competitor of GAPDH of the SIAH1 protein enhances life) is present86. NO leads to S-nitrosylation of various proteins, including GAPDH and GOSPEL. Both S-nitrosylated GOSPEL and SIAH1 can bind to S-nitrosylated GAPDH; S-nitrosylated GOSPEL inhibits the binding of S-nitrosylated GAPDH to SIAH1; thus, GAPDH is retained in the cytoplasm and nuclear transport is prevented86. Interestingly, S-nitrosylated GAPDH is considered as a nitrosylase of nuclear proteins87. As such, S-nitrosylated GAPDH nitrosylates B23/nucleophosmin at cysteine 275, a binding partner of GAPDH-SIAH1 complex in the nucleus, and induces the strong binding of B23 to SIAH1; consequently, the interaction of GAPDH with SIAH1 is disrupted88. S-nitrosylation and nuclear translocation of GAPDH can be blocked by overexpressed glutaredoxin and CGP3466B (a drug) in non-cancer cells89,90. However, the effects of these inhibitors of GAPDH S-nitrosylation on human cancer cells remain obscure.

GAPDH functions as a chaperone to protect proteins from proteasomal degradation. However, GAPDH likely loses this chaperone function when GAPDH is S-nitrosylated at Cys247 by oxidatively modified low-density lipoprotein and IFNγ91. In cancer cells, chaperones are implicated in diverse functions, such as inducing apoptosis and enhancing proliferation92,93. Despite this knowledge, the roles of GAPDH as a chaperone in cancer cells remain poorly understood.

ADP ribosylation of GAPDH promotes cell survival

GAPDH is ADP-ribosylated by transferring ADP-ribose from NAD. Arginine and cysteine are involved in modification94–96. ADP ribosylation of GAPDH is stimulated by S-nitrosylation of GAPDH97,98. In RINm5F rat tumor cells, the ADP ribosylation of GAPDH is enhanced by NO possibly because NO exhibits S-nitrosylating GAPDH function99. However, this ribosylation of GAPDH is stimulated by G-3-P via an unclear pathway100. In Entamoeba histolytica (E. histolytica), ADP-ribosylated GAPDH is found in an extracellular medium; as a result of this modification, GAPDH is incorporated in membranes, and this incorporation is the active mechanism of several bacterial toxins101. Thus, extracellular GAPDH from E. histolytica plays an essential role in interacting with host molecules and enhances the survival of this parasite in human101. ADP ribosylation catalyzed by poly-ADP-ribose polymerase (PARP) inactivates GAPDH enzyme activity and blocks glycolysis102. As glycolysis is inhibited, cells are protected from apoptosis103. In addition, PARP is associated with poor survival in cancer, and many PARP inhibitors as anticancer therapeutics are evaluated in several clinical trials104,105. Despite these findings, McDonald and Moss questioned the existence of this modification; McDonald and Moss argued that NO-stimulated, NAD-dependent modification of GAPDH is a covalent binding of the whole NAD molecule to the enzyme, not ADP ribosylation106.

Carbonylation of GAPDH enhances apoptosis

In RINm5F cells, GAPDH is carbonylated by NO; as a result, GAPDH is translocated to the nucleus and apoptosis is induced, indicating that GAPDH carbonylation is implicated in cancer cell death. Furthermore, this modification is prevented by pyridoxamine and aminoguanidine107. These data suggest the presence of new factors that can block GAPDH-mediated apoptosis.

GAPDH can be oxidized by different sunlight components. Among these components, UV-B and γ-irradiation stimulate GAPDH carbonylation in a dose-dependent manner; UV-B and γ-irradiation also enhance the participation of GAPDH in apoptosis108. This mechanism may partially explain γ-irradiation therapy in cancer109.

GAPDH acetylation also enhances the participation of GAPDH in apoptosis

Nuclear GAPDH is acetylated at Lys160 by p300 and a closely related homolog called CBP, which are among the most prominent nuclear acetyltransferases110. p300/CBP acetylates nuclear GAPDH, thereby enhancing the ability of GAPDH to stimulate auto-acetylation of p300/CBP. This result suggests a feed-forward activation cycle in which p300/CBP acetylates GAPDH and enhances the ability of GAPDH to stimulate the acetylation of p300/CBP; p300/CBP further acetylates GAPDH110. Activated p300/CBP stimulates the activation of downstream targets, including p53, and induces apoptosis111. p300/CBP-associated factor (PCAF) interacts with and acetylates GAPDH in three specific Lys residues (117, 227, and 251 in human cells); furthermore, PCAF mediates the transport of GAPDH from the cytoplasm to the nucleus; thus, apoptosis induced by nuclear translocation is enhanced112. The main PTMs of GAPDH and their effects are summarized in Figure 3.

Figure 3
Figure 3

Regulatory mechanisms of GAPDH by PTMs. GAPDH can be S-nitrosylated by NO. S-nitrosylated GAPDH (S-GAPDH) then interacts with SIAH1, and the bound GAPDH translocates to the nucleus; as a result, protein degradation is induced. In the nucleus, S-GAPDH is acetylated by p300/CBP; in turn, the auto-acetylation of p300/CBP is enhanced. Activated p300/CBP stimulates p53 gene transcription. GAPDH can also be phosphorylated by AKT; thus, the nuclear translocation of GAPDH is likely inhibited. Phosphorylated GAPDH (P-GAPDH) by PKCδ in the mitochondria blocks mitophagy. NO can induce the ADP ribosylation of GAPDH and inactivate enzyme activity; as a consequence, glycolysis is inhibited. Nevertheless, NO-induced carbonylated GAPDH (C-GAPDH) can enhance nuclear translocation. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NO, nitric oxide.

Despite the PTMs of GAPDH, many other kinds of modifications are observed. For instance, Martyniuk et al. have showed that acrylamide forms adducts with GAPDH in Cys residues (152, 156, and 247 in human cells)113. These adducted formations are correlated with GAPDH enzyme inhibition. However, the roles of adducted GAPDH in cancer cells remains unclear. Protein O-linked N-acetylglucosamine acylation (O-GlcANcylation) also occurs in GAPDH. Park and his workmates have reported that O-GlcANcylation occurs at Thr227 of GAPDH in rat cells; as a result, homo tetramer formation is disrupted and the transport of GAPDH from the cytoplasm to the nucleus is induced114. GAPDH is also S-glutathionylated in thiol groups by S-nitrosoglutathione, a NO-releasing compound115. This modification affects GAPDH participation in cell death1. Diverse PTMs of GAPDH and their functions are summarized in Table 2.

View this table:
Table 2

PTMs and their effects on GAPDH

Conclusion

GAPDH is regulated by several cancer-related factors. Moreover, PTMs, such as phosphorylation, ADP ribosylation, and acetylation, are involved in processes by which cancer cells hijack normal pathways, as well as in cancer cell development, progression, and dissemination105. Indeed, glycolysis-related factors, including GAPDH, are essential for cancer cells. As a multifunctional protein, GAPDH also influences cancer cell fate. Thus, GAPDH may be a critical regulator of cancer cell functions and a marker of cancer cell progression and prognosis.

Footnotes

  • Conflict of interest statement No potential conflicts of interest are disclosed.

  • Received November 3, 2014.
  • Accepted December 26, 2014.
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References

  1. 1.↵
    2. Colell A,
    3. Green DR,
    4. Ricci JE.
    Novel roles for GAPDH in cell death and carcinogenesis. Cell Death Differ 2009;16:1573–1581.
    OpenUrlCrossRefPubMed
  2. 2.↵
    2. Sheokand N,
    3. Malhotra H,
    4. Kumar S,
    5. Tillu VA,
    6. Chauhan AS,
    7. Raje CI, et al.
    Moonlighting cell-surface GAPDH recruits apotransferrin to effect iron egress from mammalian cells. J Cell Sci 2014;127:4279–4291.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    2. Caradec J,
    3. Sirab N,
    4. Revaud D,
    5. Keumeugni C,
    6. Loric S.
    Is GAPDH a relevant housekeeping gene for normalisation in colorectal cancer experiments? Br J Cancer 2010;103:1475–1476.
    OpenUrlPubMed
  4. 4.↵
    2. Altenberg B,
    3. Greulich KO.
    Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 2004;84:1014–1020.
    OpenUrlCrossRefPubMed
  5. 5.↵
    2. Guo C,
    3. Liu S,
    4. Sun MZ.
    Novel insight into the role of GAPDH playing in tumor. Clin Transl Oncol 2013;15:167–172.
    OpenUrlCrossRefPubMed
  6. 6.↵
    2. Nakajima H,
    3. Amano W,
    4. Fujita A,
    5. Fukuhara A,
    6. Azuma YT,
    7. Hata F, et al.
    The active site cysteine of the proapoptotic protein glyceraldehyde-3-phosphate dehydrogenase is essential in oxidative stress-induced aggregation and cell death. J Biol Chem 2007;282:26562–26574.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    2. Law ML,
    3. Kao FT.
    Regional assignment of human genes TPI1, GAPDH, LDHB, SHMT, and PEPB on chromosome 12. Cytogenet Cell Genet 1979;24:102–114.
    OpenUrlPubMed
  8. 8.↵
    2. Nicholls C,
    3. Li H,
    4. Liu JP.
    GAPDH: a common enzyme with uncommon functions. Clin Exp Pharmacol Physiol 2012;39:674–679.
    OpenUrlCrossRefPubMed
  9. 9.↵
    2. Alexander MC,
    3. Lomanto M,
    4. Nasrin N,
    5. Ramaika C.
    Insulin stimulates glyceraldehyde-3-phosphate dehydrogenase gene expression through cis-acting DNA sequences. Proc Natl Acad Sci U S A 1988;85:5092–5096.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    2. Alexander-Bridges M,
    3. Dugast I,
    4. Ercolani L,
    5. Kong XF,
    6. Giere L,
    7. Nasrin N.
    Multiple insulin-responsive elements regulate transcription of the GAPDH gene. Adv Enzyme Regul 1992;32:149–159.
    OpenUrlCrossRefPubMed
  11. 11.↵
    2. Révillion F,
    3. Pawlowski V,
    4. Hornez L,
    5. Peyrat JP.
    Glyceraldehyde-3-phosphate dehydrogenase gene expression in human breast cancer. Eur J Cancer 2000;36:1038–1042.
    OpenUrlCrossRefPubMed
  12. 12.
    2. Waxman S,
    3. Wurmbach E.
    De-regulation of common housekeeping genes in hepatocellular carcinoma. BMC Genomics 2007;8:243.
    OpenUrlCrossRefPubMed
  13. 13.↵
    2. Tang Z,
    3. Yuan S,
    4. Hu Y,
    5. Zhang H,
    6. Wu W,
    7. Zeng Z, et al.
    Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-bromopyruvate propyl ester. J Bioenerg Biomembr 2012;44:117–125.
    OpenUrlCrossRefPubMed
  14. 14.↵
    2. Chen J,
    3. Katsifis A,
    4. Hu C,
    5. Huang XF.
    Insulin decreases therapeutic efficacy in colon cancer cell line HT29 via the activation of the PI3K/Akt pathway. Curr Drug Discov Technol 2011;8:119–125.
    OpenUrlCrossRefPubMed
  15. 15.↵
    2. Chen J,
    3. Huang XF,
    4. Qiao L,
    5. Katsifis A.
    Insulin caused drug resistance to oxaliplatin in colon cancer cell line HT29. J Gastrointest Oncol 2011;2:27–33.
    OpenUrlPubMed
  16. 16.↵
    2. Baba T,
    3. Kobayashi H,
    4. Kawasaki H,
    5. Mineki R,
    6. Naito H,
    7. Ohmori D.
    Glyceraldehyde-3-phosphate dehydrogenase interacts with phosphorylated Akt resulting from increased blood glucose in rat cardiac muscle. FEBS Lett 2010;584:2796–2800.
    OpenUrlCrossRefPubMed
  17. 17.↵
    2. Jacquin MA,
    3. Chiche J,
    4. Zunino B,
    5. Beneteau M,
    6. Meynet O,
    7. Pradelli LA, et al.
    GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death. Cell Death Differ 2013;20:1043–1054.
    OpenUrlCrossRefPubMed
  18. 18.↵
    2. Ganapathy-Kanniappan S,
    3. Kunjithapatham R,
    4. Torbenson MS,
    5. Rao PP,
    6. Carson KA,
    7. Buijs M, et al.
    Human hepatocellular carcinoma in a mouse model: assessment of tumor response to percutaneous ablation by using glyceraldehyde-3-phosphate dehydrogenase antagonists. Radiology 2012;262:834–845.
    OpenUrlCrossRefPubMed
  19. 19.↵
    2. Lin JE,
    3. Li P,
    4. Snook AE,
    5. Schulz S,
    6. Dasgupta A,
    7. Hyslop TM, et al.
    The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology 2010;138:241–254.
    OpenUrlCrossRefPubMed
  20. 20.↵
    2. Kim JW,
    3. Kim TE,
    4. Kim YK,
    5. Kim YW,
    6. Kim SJ,
    7. Lee JM, et al.
    Antisense oligodeoxynucleotide of glyceraldehyde-3-phosphate dehydrogenase gene inhibits cell proliferation and induces apoptosis in human cervical carcinoma cell lines. Antisense Nucleic Acid Drug Dev 1999;9:507–513.
    OpenUrlCrossRefPubMed
  21. 21.↵
    2. Xing C,
    3. LaPorte JR,
    4. Barbay JK,
    5. Myers AG.
    Identification of GAPDH as a protein target of the saframycin antiproliferative agents. Proc Natl Acad Sci U S A 2004;101:5862–5866.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    2. Graven KK,
    3. Troxler RF,
    4. Kornfeld H,
    5. Panchenko MV,
    6. Farber HW.
    Regulation of endothelial cell glyceraldehyde-3-phosphate dehydrogenase expression by hypoxia. J Biol Chem 1994;269:24446–24453.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    2. Graven KK,
    3. Yu Q,
    4. Pan D,
    5. Roncarati JS,
    6. Farber HW.
    Identification of an oxygen responsive enhancer element in the glyceraldehyde-3-phosphate dehydrogenase gene. Biochim Biophys Acta 1999;1447:208–218.
    OpenUrlPubMed
  24. 24.↵
    2. Zhong H,
    3. Simons JW.
    Direct comparison of GAPDH, beta-actin, cyclophilin, and 28S rRNA as internal standards for quantifying RNA levels under hypoxia. Biochem Biophys Res Commun 1999;259:523–526.
    OpenUrlCrossRefPubMed
  25. 25.↵
    2. Semenza GL.
    HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000;88:1474–1480.
    OpenUrlCrossRefPubMed
  26. 26.↵
    2. Nurwidya F,
    3. Takahashi F,
    4. Minakata K,
    5. Murakami A,
    6. Takahashi K.
    From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers. Anat Cell Biol 2012;45:73–78.
    OpenUrlCrossRefPubMed
  27. 27.↵
    2. Ke X,
    3. Fei F,
    4. Chen Y,
    5. Xu L,
    6. Zhang Z,
    7. Huang Q, et al.
    Hypoxia upregulates CD147 through a combined effect of HIF-1alpha and Sp1 to promote glycolysis and tumor progression in epithelial solid tumors. Carcinogenesis 2012;33:1598–1607.
    OpenUrlCrossRefPubMed
  28. 28.↵
    2. Lee SM,
    3. Lee CT,
    4. Kim YW,
    5. Han SK,
    6. Shim YS,
    7. Yoo CG.
    Hypoxia confers protection against apoptosis via PI3K/Akt and ERK pathways in lung cancer cells. Cancer Lett 2006;242:231–238.
    OpenUrlCrossRefPubMed
  29. 29.↵
    2. Sun HL,
    3. Liu YN,
    4. Huang YT,
    5. Pan SL,
    6. Huang DY,
    7. Guh JH, et al.
    YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia. Oncogene 2007;26:3941–3951.
    OpenUrlCrossRefPubMed
  30. 30.↵
    2. Lee BL,
    3. Kim WH,
    4. Jung J,
    5. Cho SJ,
    6. Park JW,
    7. Kim J, et al.
    A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer. Carcinogenesis 2008;29:44–51.
    OpenUrlCrossRefPubMed
  31. 31.↵
    2. Manning BD,
    3. Cantley LC.
    AKT/PKB signaling: navigating downstream. Cell 2007;129:1261–1274.
    OpenUrlCrossRefPubMed
  32. 32.↵
    2. Vander Heiden MG,
    3. Cantley LC,
    4. Thompson CB.
    Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029–1033.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    2. He Q,
    3. Gao Z,
    4. Yin J,
    5. Zhang J,
    6. Yun Z,
    7. Ye J.
    Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab 2011;300:E877–885.
    OpenUrlCrossRefPubMed
  34. 34.↵
    2. Wang F,
    3. Li SS,
    4. Segersvard R,
    5. Strommer L,
    6. Sundqvist KG,
    7. Holgersson J, et al.
    Hypoxia inducible factor-1 mediates effects of insulin on pancreatic cancer cells and disturbs host energy homeostasis. Am J Pathol 2007;170:469–477.
    OpenUrlCrossRefPubMed
  35. 35.↵
    2. Roth U,
    3. Curth K,
    4. Unterman TG,
    5. Kietzmann T.
    The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 2004;279:2623–2631.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    2. Chen RW,
    3. Saunders PA,
    4. Wei H,
    5. Li Z,
    6. Seth P,
    7. Chuang DM.
    Involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and p53 in neuronal apoptosis: evidence that GAPDH is upregulated by p53. J Neurosci 1999;19:9654–9662.
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    2. Madan E,
    3. Gogna R,
    4. Bhatt M,
    5. Pati U,
    6. Kuppusamy P,
    7. Mahdi AA.
    Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. Oncotarget 2011;2:948–957.
    OpenUrlCrossRefPubMed
  38. 38.↵
    2. Fiucci G,
    3. Beaucourt S,
    4. Duflaut D,
    5. Lespagnol A,
    6. Stumptner-Cuvelette P,
    7. Geant A, et al.
    Siah-1b is a direct transcriptional target of p53: Identification of the functional p53 responsive element in the siah-1b promoter. Proceedings of the National Academy of Sciences of the United States of America 2004;101:3510–3515.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    2. Reed JC,
    3. Ely KR.
    Degrading liaisons: Siah structure revealed. Nat Struct Biol 2002;9:8–10.
    OpenUrlCrossRefPubMed
  40. 40.↵
    2. Hara MR,
    3. Agrawal N,
    4. Kim SF,
    5. Cascio MB,
    6. Fujimuro M,
    7. Ozeki Y, et al.
    S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 2005;7:665–674.
    OpenUrlCrossRefPubMed
  41. 41.↵
    2. Hara MR,
    3. Snyder SH.
    Nitric oxide-GAPDH-Siah: a novel cell death cascade. Cell Mol Neurobiol 2006;26:527–538.
    OpenUrlCrossRefPubMed
  42. 42.↵
    2. Thangima Zannat M,
    3. Bhattacharjee RB,
    4. Bag J.
    In the absence of cellular poly (A) binding protein, the glycolytic enzyme GAPDH translocated to the cell nucleus and activated the GAPDH mediated apoptotic pathway by enhancing acetylation and serine 46 phosphorylation of p53. Biochem Biophys Res Commun 2011;409:171–176.
    OpenUrlCrossRefPubMed
  43. 43.↵
    2. Zhai D,
    3. Chin K,
    4. Wang M,
    5. Liu F.
    Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage. Mol Brain 2014;7:20.
    OpenUrlCrossRefPubMed
  44. 44.↵
    2. Huang Q,
    3. Lan F,
    4. Zheng Z,
    5. Xie F,
    6. Han J,
    7. Dong L, et al.
    Akt2 kinase suppresses glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-mediated apoptosis in ovarian cancer cells via phosphorylating GAPDH at threonine 237 and decreasing its nuclear translocation. J Biol Chem 2011;286:42211–42220.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    2. Leisner TM,
    3. Moran C,
    4. Holly SP,
    5. Parise LV.
    CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling. Oncogene 2013;32:4017–27.
    OpenUrlCrossRefPubMed
  46. 46.↵
    2. Yang X,
    3. Fraser M,
    4. Moll UM,
    5. Basak A,
    6. Tsang BK.
    Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res 2006;66:3126–3136.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    2. Zhou Y,
    3. Wang SY,
    4. Yang XK,
    5. Wang HM.
    [Relationship between the Akt-regulated direct p53 mitochondrial translocation and the resistance to cisplatin of ovarian cancer cells]. Zhonghua Zhong Liu Za Zhi 2011;33:97–100.
    OpenUrlPubMed
  48. 48.↵
    2. Tarze A,
    3. Deniaud A,
    4. Le Bras M,
    5. Maillier E,
    6. Molle D,
    7. Larochette N, et al.
    GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. Oncogene 2007;26:2606–2620.
    OpenUrlCrossRefPubMed
  49. 49.↵
    2. Colell A,
    3. Ricci JE,
    4. Tait S,
    5. Milasta S,
    6. Maurer U,
    7. Bouchier-Hayes L, et al.
    GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 2007;129:983–997.
    OpenUrlCrossRefPubMed
  50. 50.↵
    2. Ricci JE,
    3. Munoz-Pinedo C,
    4. Fitzgerald P,
    5. Bailly-Maitre B,
    6. Perkins GA,
    7. Yadava N, et al.
    Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 2004;117:773–786.
    OpenUrlCrossRefPubMed
  51. 51.↵
    2. Soltany-Rezaee-Rad M,
    3. Mottaghi-Dastjerdi N,
    4. Setayesh N,
    5. Roshandel G,
    6. Ebrahimifard F,
    7. Sepehrizadeh Z.
    Overexpression of FOXO3, MYD88, and GAPDH Identified by Suppression Subtractive Hybridization in Esophageal Cancer Is Associated with Autophagy. Gastroenterol Res Pract 2014;2014:185035.
  52. 52.↵
    2. Chen YW,
    3. Chenier I,
    4. Chang SY,
    5. Tran S,
    6. Ingelfinger JR,
    7. Zhang SL.
    High glucose promotes nascent nephron apoptosis via NF-kappaB and p53 pathways. Am J Physiol Renal Physiol 2011;300:F147–F156.
    OpenUrlCrossRefPubMed
  53. 53.↵
    2. Akca H,
    3. Yenisoy S,
    4. Yanikoglu A,
    5. Ozes ON.
    Tumor necrosis factor-alpha-induced accumulation of tumor suppressor protein p53 and cyclin-dependent protein kinase inhibitory protein p21 is inhibited by insulin in ME-180S cells. Clin Chem Lab Med 2002;40:764–768.
    OpenUrlPubMed
  54. 54.↵
    2. Grimberg A,
    3. Coleman CM,
    4. Burns TF,
    5. Himelstein BP,
    6. Koch CJ,
    7. Cohen P, et al.
    p53-Dependent and p53-independent induction of insulin-like growth factor binding protein-3 by deoxyribonucleic acid damage and hypoxia. J Clin Endocrinol Metab 2005;90:3568–3574.
    OpenUrlCrossRefPubMed
  55. 55.↵
    2. Kimura S,
    3. Kitadai Y,
    4. Kuwai T,
    5. Tanaka S,
    6. Hihara J,
    7. Yoshida K, et al.
    Expression of p53 protein in esophageal squamous cell carcinoma: relation to hypoxia-inducible factor-1alpha, angiogenesis and apoptosis. Pathobiology 2005;72:179–185.
    OpenUrlPubMed
  56. 56.↵
    2. Ao JE,
    3. Kuang LH,
    4. Zhou Y,
    5. Zhao R,
    6. Yang CM.
    Hypoxia-inducible factor 1 regulated ARC expression mediated hypoxia induced inactivation of the intrinsic death pathway in p53 deficient human colon cancer cells. Biochem Biophys Res Commun 2012;420:913–917.
    OpenUrlCrossRefPubMed
  57. 57.↵
    2. Bereta J,
    3. Bereta M.
    Stimulation of glyceraldehyde-3-phosphate dehydrogenase mRNA levels by endogenous nitric oxide in cytokine-activated endothelium. Biochem Biophys Res Commun 1995;217:363–369.
    OpenUrlCrossRefPubMed
  58. 58.↵
    2. Ortiz-Ortiz MA,
    3. Moran JM,
    4. Ruiz-Mesa LM,
    5. Bravo-San Pedro JM,
    6. Fuentes JM.
    Paraquat exposure induces nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the activation of the nitric oxide-GAPDH-Siah cell death cascade. Toxicol Sci 2010;116:614–622.
    OpenUrlCrossRefPubMed
  59. 59.↵
    2. Messmer UK,
    3. Brune B.
    Modification of macrophage glyceraldehyde-3-phosphate dehydrogenase in response to nitric oxide. Eur J Pharmacol 1996;302:171–182.
    OpenUrlCrossRefPubMed
  60. 60.↵
    2. Sang J,
    3. Chen Y,
    4. Tao Y.
    Nitric oxide inhibits gastric cancer cell growth through the modulation of the Akt pathway. Mol Med Rep 2011;4:1163–1167.
    OpenUrl
  61. 61.↵
    2. Kielbik M,
    3. Klink M,
    4. Brzezinska M,
    5. Szulc I,
    6. Sulowska Z.
    Nitric oxide donors: spermine/NO and diethylenetriamine/NO induce ovarian cancer cell death and affect STAT3 and AKT signaling proteins. Nitric Oxide 2013;35:93–109.
    OpenUrlCrossRef
  62. 62.↵
    2. Guha M,
    3. Biswas J,
    4. Tirkey J,
    5. Sinha AK.
    Impairment of stimulation by estrogen of insulin-activated nitric oxide synthase in human breast cancer. Int J Cancer 2002;100:261–265.
    OpenUrlPubMed
  63. 63.↵
    2. Mortensen K,
    3. Skouv J,
    4. Hougaard DM,
    5. Larsson LI.
    Endogenous endothelial cell nitric-oxide synthase modulates apoptosis in cultured breast cancer cells and is transcriptionally regulated by p53. J Biol Chem 1999;274:37679–37684.
    OpenUrlAbstract/FREE Full Text
  64. 64.↵
    2. Yasuda H.
    Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer. Nitric Oxide 2008;19:205–216.
    OpenUrlCrossRefPubMed
  65. 65.↵
    2. Appelskog IB,
    3. Ammerpohl O,
    4. Svechnikova IG,
    5. Lui WO,
    6. Almqvist PM,
    7. Ekstrom TJ.
    Histone deacetylase inhibitor 4-phenylbutyrate suppresses GAPDH mRNA expression in glioma cells. Int J Oncol 2004;24:1419–1425.
    OpenUrlPubMed
  66. 66.↵
    2. Kanai H,
    3. Sawa A,
    4. Chen RW,
    5. Leeds P,
    6. Chuang DM.
    Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics J 2004;4:336–344.
    OpenUrlCrossRefPubMed
  67. 67.↵
    2. Rao R,
    3. Fiskus W,
    4. Ganguly S,
    5. Kambhampati S,
    6. Bhalla KN.
    HDAC inhibitors and chaperone function. Adv Cancer Res 2012;116:239–262.
    OpenUrlCrossRefPubMed
  68. 68.↵
    2. Mimori S,
    3. Ohtaka H,
    4. Koshikawa Y,
    5. Kawada K,
    6. Kaneko M,
    7. Okuma Y, et al.
    4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor. Bioorg Med Chem Lett 2013;23:6015–6018.
    OpenUrl
  69. 69.↵
    2. Tong V,
    3. Teng XW,
    4. Chang TK,
    5. Abbott FS.
    Valproic acid II: effects on oxidative stress, mitochondrial membrane potential, and cytotoxicity in glutathione-depleted rat hepatocytes. Toxicol Sci 2005;86:436–443.
    OpenUrlCrossRefPubMed
  70. 70.↵
    2. Nott A,
    3. Watson PM,
    4. Robinson JD,
    5. Crepaldi L,
    6. Riccio A.
    S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 2008;455:411–415.
    OpenUrlCrossRefPubMed
  71. 71.↵
    2. Sen N,
    3. Snyder SH.
    Neurotrophin-mediated degradation of histone methyltransferase by S-nitrosylation cascade regulates neuronal differentiation. Proc Natl Acad Sci U S A 2011;108:20178–20183.
    OpenUrlAbstract/FREE Full Text
  72. 72.↵
    2. Zheng L,
    3. Roeder RG,
    4. Luo Y.
    S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell 2003;114:255–266.
    OpenUrlCrossRefPubMed
  73. 73.↵
    2. Wang D,
    3. Moothart DR,
    4. Lowy DR,
    5. Qian X.
    The expression of glyceraldehyde-3-phosphate dehydrogenase associated cell cycle (GACC) genes correlates with cancer stage and poor survival in patients with solid tumors. PLoS One 2013;8:e61262.
  74. 74.↵
    2. Lee JV,
    3. Carrer A,
    4. Shah S,
    5. Snyder NW,
    6. Wei S,
    7. Venneti S, et al.
    Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab 2014;20:306–319.
    OpenUrlCrossRefPubMed
  75. 75.↵
    2. Seo J,
    3. Jeong J,
    4. Kim YM,
    5. Hwang N,
    6. Paek E,
    7. Lee KJ.
    Strategy for comprehensive identification of post-translational modifications in cellular proteins, including low abundant modifications: application to glyceraldehyde-3-phosphate dehydrogenase. J Proteome Res 2008;7:587–602.
    OpenUrlCrossRefPubMed
  76. 76.↵
    2. Tisdale EJ.
    Glyceraldehyde-3-phosphate dehydrogenase is phosphorylated by protein kinase Ciota /lambda and plays a role in microtubule dynamics in the early secretory pathway. J Biol Chem 2002;277:3334–3341.
    OpenUrlAbstract/FREE Full Text
  77. 77.↵
    2. Tisdale EJ.
    Glyceraldehyde-3-phosphate dehydrogenase is required for vesicular transport in the early secretory pathway. J Biol Chem 2001;276:2480–2486.
    OpenUrlAbstract/FREE Full Text
  78. 78.↵
    2. Tisdale EJ,
    3. Azizi F,
    4. Artalejo CR.
    Rab2 utilizes glyceraldehyde-3-phosphate dehydrogenase and protein kinase C{iota} to associate with microtubules and to recruit dynein. J Biol Chem 2009;284:5876–5884.
    OpenUrlAbstract/FREE Full Text
  79. 79.↵
    2. Tisdale EJ.
    Rab2 interacts directly with atypical protein kinase C (aPKC) iota/lambda and inhibits aPKCiota/lambda-dependent glyceraldehyde-3-phosphate dehydrogenase phosphorylation. J Biol Chem 2003;278:52524–52530.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    2. Glaser PE,
    3. Han X,
    4. Gross RW.
    Tubulin is the endogenous inhibitor of the glyceraldehyde 3-phosphate dehydrogenase isoform that catalyzes membrane fusion: Implications for the coordinated regulation of glycolysis and membrane fusion. Proc Natl Acad Sci U S A 2002;99:14104–14109.
    OpenUrlAbstract/FREE Full Text
  81. 81.↵
    2. Tisdale EJ,
    3. Artalejo CR.
    A GAPDH mutant defective in Src-dependent tyrosine phosphorylation impedes Rab2-mediated events. Traffic 2007;8:733–741.
    OpenUrlCrossRefPubMed
  82. 82.↵
    2. Daubenberger CA,
    3. Tisdale EJ,
    4. Curcic M,
    5. Diaz D,
    6. Silvie O,
    7. Mazier D, et al.
    The N’-terminal domain of glyceraldehyde-3-phosphate dehydrogenase of the apicomplexan Plasmodium falciparum mediates GTPase Rab2-dependent recruitment to membranes. Biol Chem 2003;384:1227–1237.
    OpenUrlCrossRefPubMed
  83. 83.↵
    2. Yogalingam G,
    3. Hwang S,
    4. Ferreira JC,
    5. Mochly-Rosen D.
    Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) phosphorylation by protein kinase Cdelta (PKCdelta) inhibits mitochondria elimination by lysosomal-like structures following ischemia and reoxygenation-induced injury. J Biol Chem 2013;288:18947–18960.
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    2. Chakravarti R,
    3. Aulak KS,
    4. Fox PL,
    5. Stuehr DJ.
    GAPDH regulates cellular heme insertion into inducible nitric oxide synthase. Proc Natl Acad Sci U S A 2010;107:18004–18009.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    2. Lee SY,
    3. Kim JH,
    4. Jung H,
    5. Chi SW,
    6. Chung SJ,
    7. Lee CK, et al.
    Glyceraldehyde-3-phosphate, a glycolytic intermediate, prevents cells from apoptosis by lowering S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase. J Microbiol Biotechnol 2012;22:571–573.
    OpenUrlPubMed
  86. 86.↵
    2. Sen N,
    3. Hara MR,
    4. Ahmad AS,
    5. Cascio MB,
    6. Kamiya A,
    7. Ehmsen JT, et al.
    GOSPEL: a neuroprotective protein that binds to GAPDH upon S-nitrosylation. Neuron 2009;63:81–91.
    OpenUrlCrossRefPubMed
  87. 87.↵
    2. Kornberg MD,
    3. Sen N,
    4. Hara MR,
    5. Juluri KR,
    6. Nguyen JV,
    7. Snowman AM, et al.
    GAPDH mediates nitrosylation of nuclear proteins. Nat Cell Biol 2010;12:1094–1100.
    OpenUrlCrossRefPubMed
  88. 88.↵
    2. Lee SB,
    3. Kim CK,
    4. Lee KH,
    5. Ahn JY.
    S-nitrosylation of B23/nucleophosmin by GAPDH protects cells from the SIAH1-GAPDH death cascade. J Cell Biol 2012;199:65–76.
    OpenUrlAbstract/FREE Full Text
  89. 89.↵
    2. Inadomi C,
    3. Murata H,
    4. Ihara Y,
    5. Goto S,
    6. Urata Y,
    7. Yodoi J, et al.
    Overexpression of glutaredoxin protects cardiomyocytes against nitric oxide-induced apoptosis with suppressing the S-nitrosylation of proteins and nuclear translocation of GAPDH. Biochem Biophys Res Commun 2012;425:656–661.
    OpenUrlPubMed
  90. 90.↵
    2. Xu R,
    3. Serritella AV,
    4. Sen T,
    5. Farook JM,
    6. Sedlak TW,
    7. Baraban J, et al.
    Behavioral effects of cocaine mediated by nitric oxide-GAPDH transcriptional signaling. Neuron 2013;78:623–630.
    OpenUrlCrossRefPubMed
  91. 91.↵
    2. Jia J,
    3. Arif A,
    4. Willard B,
    5. Smith JD,
    6. Stuehr DJ,
    7. Hazen SL, et al.
    Protection of extraribosomal RPL13a by GAPDH and dysregulation by S-nitrosylation. Mol Cell 2012;47:656–663.
    OpenUrlCrossRefPubMed
  92. 92.↵
    2. Ohnishi K,
    3. Ota I,
    4. Yane K,
    5. Takahashi A,
    6. Yuki K,
    7. Emoto M, et al.
    Glycerol as a chemical chaperone enhances radiation-induced apoptosis in anaplastic thyroid carcinoma cells. Mol Cancer 2002;1:4.
    OpenUrlCrossRefPubMed
  93. 93.↵
    2. Cai H,
    3. Peng F.
    Knockdown of copper chaperone antioxidant-1 by RNA interference inhibits copper-stimulated proliferation of non-small cell lung carcinoma cells. Oncol Rep 2013;30:269–275.
    OpenUrlPubMed
  94. 94.↵
    2. Deveze-Alvarez M,
    3. Garcia-Soto J,
    4. Martinez-Cadena G.
    Glyceraldehyde-3-phosphate dehydrogenase is negatively regulated by ADP-ribosylation in the fungus Phycomyces blakesleeanus. Microbiology 2001;147:2579–2584.
    OpenUrlPubMed
  95. 95.
    2. Zhang J,
    3. Snyder SH.
    Nitric oxide stimulates auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U S A 1992;89:9382–9385.
    OpenUrlAbstract/FREE Full Text
  96. 96.↵
    2. Kots AYa,
    3. Skurat AV,
    4. Sergienko EA,
    5. Bulargina TV,
    6. Severin ES.
    Nitroprusside stimulates the cysteine-specific mono(ADP-ribosylation) of glyceraldehyde-3-phosphate dehydrogenase from human erythrocytes. FEBS Lett 1992;300:9–12.
    OpenUrlCrossRefPubMed
  97. 97.↵
    2. Dimmeler S,
    3. Brune B.
    Characterization of a nitric-oxide-catalysed ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. Eur J Biochem 1992;210:305–310.
    OpenUrlPubMed
  98. 98.↵
    2. Molina y Vedia L,
    3. McDonald B,
    4. Reep B,
    5. Brune B,
    6. Di Silvio M,
    7. Billiar TR, et al.
    Nitric oxide-induced S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits enzymatic activity and increases endogenous ADP-ribosylation. J Biol Chem 1992;267:24929–24932.
    OpenUrlAbstract/FREE Full Text
  99. 99.↵
    2. Dimmeler S,
    3. Ankarcrona M,
    4. Nicotera P,
    5. Brune B.
    Exogenous nitric oxide (NO) generation or IL-1 beta-induced intracellular NO production stimulates inhibitory auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase in RINm5F cells. J Immunol 1993;150:2964–2971.
    OpenUrlAbstract
  100. 100.↵
    2. Kots AYa,
    3. Sergienko EA,
    4. Bulargina TV,
    5. Severin ES.
    Glyceraldehyde-3-phosphate activates auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. FEBS Lett 1993;324:33–36.
    OpenUrlCrossRefPubMed
  101. 101.↵
    2. Alvarez AH,
    3. Martinez-Cadena G,
    4. Silva ME,
    5. Saavedra E,
    6. Avila EE.
    Entamoeba histolytica: ADP-ribosylation of secreted glyceraldehyde-3-phosphate dehydrogenase. Exp Parasitol 2007;117:349–356.
    OpenUrlCrossRefPubMed
  102. 102.↵
    2. Dimmeler S,
    3. Lottspeich F,
    4. Brune B.
    Nitric oxide causes ADP-ribosylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem 1992;267:16771–16774.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    2. Colussi C,
    3. Albertini MC,
    4. Coppola S,
    5. Rovidati S,
    6. Galli F,
    7. Ghibelli L.
    H2O2-induced block of glycolysis as an active ADP-ribosylation reaction protecting cells from apoptosis. FASEB J 2000;14:2266–2276.
    OpenUrlCrossRefPubMed
  104. 104.↵
    2. Rojo F,
    3. Garcia-Parra J,
    4. Zazo S,
    5. Tusquets I,
    6. Ferrer-Lozano J,
    7. Menendez S, et al.
    Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol 2012;23:1156–1164.
    OpenUrlCrossRefPubMed
  105. 105.↵
    2. Scarpa ES,
    3. Fabrizio G,
    4. Di Girolamo M.
    A role of intracellular mono-ADP-ribosylation in cancer biology. FEBS J 2013;280:3551–3562.
    OpenUrlCrossRefPubMed
  106. 106.↵
    2. McDonald LJ,
    3. Moss J.
    Nitric oxide and NAD-dependent protein modification. Mol Cell Biochem 1994;138:201–206.
    OpenUrlCrossRefPubMed
  107. 107.↵
    2. Cahuana GM,
    3. Tejedo JR,
    4. Jimenez J,
    5. Ramirez R,
    6. Sobrino F,
    7. Bedoya FJ.
    Nitric oxide-induced carbonylation of Bcl-2, GAPDH and ANT precedes apoptotic events in insulin-secreting RINm5F cells. Exp Cell Res 2004;293:22–30.
    OpenUrlCrossRefPubMed
  108. 108.↵
    2. Voss P,
    3. Hajimiragha H,
    4. Engels M,
    5. Ruhwiedel C,
    6. Calles C,
    7. Schroeder P, et al.
    Irradiation of GAPDH: a model for environmentally induced protein damage. Biol Chem 2007;388:583–592.
    OpenUrlCrossRefPubMed
  109. 109.↵
    2. Huang Z,
    3. Jiang J,
    4. Belikova NA,
    5. Stoyanovsky DA,
    6. Kagan VE,
    7. Mintz AH.
    Protection of normal brain cells from gamma-irradiation-induced apoptosis by a mitochondria-targeted triphenyl-phosphonium-nitroxide: a possible utility in glioblastoma therapy. J Neurooncol 2010;100:1–8.
    OpenUrlPubMed
  110. 110.↵
    2. Sen N,
    3. Hara MR,
    4. Kornberg MD,
    5. Cascio MB,
    6. Bae BI,
    7. Shahani N, et al.
    Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol 2008;10:866–873.
    OpenUrlCrossRefPubMed
  111. 111.↵
    2. Kim WJ,
    3. Rivera MN,
    4. Coffman EJ,
    5. Haber DA.
    The WTX tumor suppressor enhances p53 acetylation by CBP/p300. Mol Cell 2012;45:587–597.
    OpenUrlCrossRefPubMed
  112. 112.↵
    2. Ventura M,
    3. Mateo F,
    4. Serratosa J,
    5. Salaet I,
    6. Carujo S,
    7. Bachs O, et al.
    Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase is regulated by acetylation. Int J Biochem Cell Biol 2010;42:1672–1680.
    OpenUrlCrossRefPubMed
  113. 113.↵
    2. Martyniuk CJ,
    3. Fang B,
    4. Koomen JM,
    5. Gavin T,
    6. Zhang L,
    7. Barber DS, et al.
    Molecular mechanism of glyceraldehyde-3-phosphate dehydrogenase inactivation by alpha,beta-unsaturated carbonyl derivatives. Chem Res Toxicol 2011;24:2302–2311.
    OpenUrlCrossRefPubMed
  114. 114.↵
    2. Park J,
    3. Han D,
    4. Kim K,
    5. Kang Y,
    6. Kim Y.
    O-GlcNAcylation disrupts glyceraldehyde-3-phosphate dehydrogenase homo-tetramer formation and mediates its nuclear translocation. Biochim Biophys Acta 2009;1794:254–262.
    OpenUrlCrossRefPubMed
  115. 115.↵
    2. Mohr S,
    3. Hallak H,
    4. de Boitte A,
    5. Lapetina EG,
    6. Brune B.
    Nitric oxide-induced S-glutathionylation and inactivation of glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem 1999;274:9427–9430.
    OpenUrlAbstract/FREE Full Text
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