Limits...
Critical protein GAPDH and its regulatory mechanisms in cancer cells.

Zhang JY, Zhang F, Hong CQ, Giuliano AE, Cui XJ, Zhou GJ, Zhang GJ, Cui YK - Cancer Biol Med (2015)

Bottom Line: 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.In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized.

View Article: PubMed Central - PubMed

Affiliation: 1 Department of Physiology, Guangdong Medical College, Dongguan 523808, China ; 2 Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou 515041, China ; 3 Department of Surgery, Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4383849&req=5

f2: 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.

Mentions: 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).


Critical protein GAPDH and its regulatory mechanisms in cancer cells.

Zhang JY, Zhang F, Hong CQ, Giuliano AE, Cui XJ, Zhou GJ, Zhang GJ, Cui YK - Cancer Biol Med (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383849&req=5

f2: 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.
Mentions: 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).

Bottom Line: 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.In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized.

View Article: PubMed Central - PubMed

Affiliation: 1 Department of Physiology, Guangdong Medical College, Dongguan 523808, China ; 2 Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou 515041, China ; 3 Department of Surgery, Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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.

No MeSH data available.


Related in: MedlinePlus