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

Huang, Qiuyuan; Lan, Fenghua; Zheng, Zhiyong; Xie, Fang-Fang; Han, Junyong; Dong, Lihong; Xie, Yanchuan; Zhao, Feng

doi:10.1074/jbc.m111.296905

Cited by 86 publications

(75 citation statements)

References 39 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate a potential role of GAPDH in telomere maintenance in breast cancer cells, we expressed recombinant GAPDH in MCF7 cells. Whereas we noted a reduced cell density in the MCF7 cell cultures stably expressing GFP-GAPDH consistent with previous findings of GAPDH-induced cancer cell death (3,4,7,25,28,29), we found that there were significant changes in the morphology of Author contributions: C.N., A.R.P., H.L., and J.-P.L. designed research; C.N., A.R.P., L.L., R.S., and L.W.…”

Section: Resultssupporting

confidence: 92%

See 1 more Smart Citation

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

Nicholls

Pinto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD + binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance. Furthermore, the GAPDH substrate glyceraldehyde-3-phosphate (G3P) and the nitric oxide donor S-nitrosoglutathione (GSNO) both negatively regulate GAPDH inhibition of telomerase activity. Thus, we demonstrate that GAPDH is regulated to target the telomerase complex, resulting in an arrest of telomere maintenance and cancer cell proliferation. and apoptosis. Although production of daughter cells costs energy, it remains largely elusive how energy metabolism regulates normal cell aging and lifespan. Considerable evidence suggests that metabolic waste causes premature senescence and apoptosis, shortening cellular lifespan. Accumulation of reactive oxygen species (ROS) damages cellular enzymes, organelle membranes, and chromosomal DNA including telomeres (the ends of chromosomes) (1, 2). Whereas enzymes that reduce the production of metabolic hazards may operate to extend cellular lifespan, recent studies demonstrate that the energy producing enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that limits ROS production undergoes structural modifications and travel into the nucleus (3-7) to interact with telomeres directly and to potentially alleviate stress-induced cell aging (8, 9).Human telomeres are composed of arrays of a few thousand tandem DNA repeats of TTAGGG and various binding proteins. Telomeres undergo progressive shortening as somatic cells divide, due to the inability of cells to replicate the extreme ends of chromosomes. When telomeres are critically short, cells exit the cell cycle and undergo cell senescence (10-13). As a measure to maintain telomeres for continuous renewal of germ lines, development of embryonic stem cells, clonal expansion of lymphocytes, and immortalization of neoplastic cells, telomerase is activated to synthesize and maintain telomeres by reverse transcription (10-13).Telomerase is a large ribonucleoprotein complex containing the catalytic subunit telomerase reverse transcriptase (TERT) and an RNA template (reviewed in refs. 13 and 14). Human telomerase reverse transcriptase (hTERT) comprises 1,132 amino acid residues and human telomerase RNA (hTERC) is composed of 451 nucleotides (15-18). Reconstitution of telomerase activity in telomerase-negative cells can be achieved by expression of hTERT, demonstrating that hTERT is the rate-limiting component of the enzyme complex (19,20).GAPDH has long been recognize...

show abstract

Section: Resultssupporting

confidence: 92%

“…5,[22][23][24]. A large body of evidence indicates that GAPDH responds to various stress insults by translocation to the nucleus (3)(4)(5)(6)(7)25). In the nucleus, GAPDH is the key component of a gene transcriptosome for cell division (6).…”

mentioning

confidence: 99%

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

Nicholls

Pinto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…This mutation was proposed to mimic the posttranslational OGlcNacylation of Thr-229 by O-GlcNac transferase (57), but it is not known whether this GAPDH modification regulates RNA binding. Other posttranslational modifications of GAPDH have been identified near the dimer interface, including acetylation (58,72), phosphorylation (59,60), and O-GlcNacylation by other glycosyltransferases (73). In some cases, these modifications have been shown to alter GAPDH localization, interaction with other proteins, and possibly its oligomerization state.…”

Section: Discussionmentioning

confidence: 99%

A Dimer Interface Mutation in Glyceraldehyde-3-Phosphate Dehydrogenase Regulates Its Binding to AU-rich RNA

White

Khan

Deredge

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The glycolytic enzyme GAPDH is a non-canonical RNA-binding protein.Results: A dimer interface mutation impairs the two-step binding of GAPDH to AU-rich elements from TNF-␣ mRNA and leads to RNA structural changes. Conclusion: Dimer and tetramer interface residues are important for GAPDH-RNA binding. Significance: We propose a novel model for GAPDH binding to AU-rich RNA via the oligomeric interfaces.

show abstract

“…In this direction, recent reports indicate that GAPDH can modulate the PI3K pathway 38 and that GAPDH has the ability to interact with Akt in other settings. 39,40 Therefore, once stabilized by GAPDH, activated Akt leads to FoxO phosphorylation (Figure 1a), preventing its nuclear relocalization and resulting in Bcl-6 downregulation (Figures 7a and b). Decrease of this transcriptional inhibitor leads to enhancement of Bcl-xL expression (Figures 7a, b, c, g and h) and clonogenic outgrowth from CICD (Figure 7i).…”

Section: Discussionmentioning

confidence: 99%

GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death

Chiche

Zunino

et al. 2013

Cell Death Differ

View full text Add to dashboard Cite

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

Cited by 86 publications

References 39 publications

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

A Dimer Interface Mutation in Glyceraldehyde-3-Phosphate Dehydrogenase Regulates Its Binding to AU-rich RNA

GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death

Contact Info

Product

Resources

About