Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

Zhang, Jinlong; Feng, Guoliang; Bao, Guofeng; Xu, Guanhua; Sun, Yuyu; Li, Weidong; Wang, Lingling; Chen, Jiajia; Jin, Huricha; Cui, Zhiming

doi:10.1080/15384101.2015.1064203

Cited by 39 publications

(22 citation statements)

References 49 publications

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“…The data presented here show that in control cells, pY-containing HuR is predominantly a nuclear protein, and that forms of PKM2 that retain pY-binding ability co-immunoprecipitate with HuR as well as rescue cells from defects in cell cycle progression caused by PKM2 knock-down. The accumulation of HuR in the cytoplasm following suppression of PKM2 levels also supports the idea that PKM2 binds and traps HuR, and in particular pY-containing HuR (as well as possibly p27 itself) 47 in the nucleus, limiting the ability of HuR to facilitate p27 mRNA translation in the cytoplasm. Under these conditions the trapped nuclear HuR may be able to function as a progrowth regulator of splicing and a stabilizer of nuclear pre-mRNAs involved in stimulating cell growth, 38 including PKM2.…”

Section: Novel Links Between Pkm2 Hur P27 and Cell Cycle Arrestsupporting

confidence: 60%

PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells

Mukherjee

Ohba

See

2016

Intl Journal of Cancer

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The M2 isoform of pyruvate kinase (PK) is upregulated in most cancers including glioblastoma. Although PKM2 has been reported to use dual kinase activities to regulate cell growth, it also interacts with phosphotyrosine (pY)-containing peptides independently of its kinase activity. The potential for PKM2 to use the binding of pY-containing proteins to control tumor growth has not been fully examined. We here describe a novel mechanism by which PKM2 interacts in the nucleus with the RNA binding protein HuR to regulate HuR sub-cellular localization, p27 levels, cell cycle progression and glioma cell growth. Suppression of PKM2 in U87, T98G and LN319 glioma cells resulted in increased p27 levels, defects in entry into mitosis, increased centrosome number, and decreased cell growth. These effects could be reversed by shRNA targeting p27. The increased levels of p27 in PKM2 knock-down cells were caused by a loss of the nuclear interaction between PKM2 and HuR, and a subsequent cytoplasmic re-distribution of HuR, which in turn led to increased cap-independent p27 mRNA translation. Consistent with these results, the alterations in p27 mRNA translation, cell cycle progression and cell growth caused by PKM2 suppression could be reversed in vitro and in vivo by suppression of HuR or p27 levels, or by introduction of forms of PKM2 that could bind pY, regardless of their kinase activity. These results define a novel mechanism by which PKM2 regulates glioma cell growth, and also define a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway.Pyruvate kinase (PK) is an enzyme that catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate in the final and rate-limiting step of glycolysis. 1 PK is expressed in four isoforms, L, R, M1 and M2. 2 PKML and PKMR have a limited, tissue-specific pattern of expression, being expressed in liver and erythrocytes, respectively. PKM1 in contrast is expressed in tissues thought to have high energy requirements such as skeletal muscle and brain. 3 PKM1 forms homotetramers, which have a high affinity for PEP and generate high levels of pyruvate, 2 which in turn is funneled into the citric acid cycle for further production of energy. 2 PKM2 in contrast, is expressed in many differentiated tissues as well as in cells with a high rate of nucleic acid synthesis such as stem cells and many (but not all) tumors, including gliomas. 4,5 In these tissues PKM2 exists in both tetrameric and monomeric/dimeric forms. 6 The tetrameric form of PKM2 is the most active with regard to PK activity. 2 In tumors, however, growth-related signaling events lead to phosphorylation of PKM2 at Y105, 7 and increased binding of PKM2 to phospho-tyrosine (pY)-containing proteins. 8 These events, along with low levels of the PKM2 allosteric activator fructose 1,6 -bisphosphate, limit tetramer formation, limit PK activity, and in turn are associated with increased tumor growth. 2,4,7,8 Consistent with this idea, the complete deletion of PKM2 in models of breast cancer results in increased tumor gro...

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Section: Novel Links Between Pkm2 Hur P27 and Cell Cycle Arrestsupporting

confidence: 60%

PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells

Mukherjee

Ohba

See

2016

Intl Journal of Cancer

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“…The different results might be related to the different time point after SCI because SCI includes complex physiological and biochemical mechanisms. Various proteins are increased immediately after SCI to compensate for the injury and then decreased with the passage of time [32]. Our results also showed that MDSCs could promote β -catenin, which is downregulated in injured neurons.…”

Section: Discussionsupporting

confidence: 52%

The Neuroprotective Effects of Muscle-Derived Stem Cells via Brain-Derived Neurotrophic Factor in Spinal Cord Injury Model

Han

Chen

Fang

et al. 2017

BioMed Research International

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Muscle-derived stem cells (MDSCs) possess multipotent differentiation and self-renewal capacities; however, the effects and mechanism in neuron injury remain unclear. The aim of this study was to investigate the effects of MDSCs on neuron secondary injury, oxidative stress-induced apoptosis. An in vivo study showed the Basso, Beattie, and Bresnahan (BBB) score and number of neurons significantly increased after MDSCs' transplantation in spinal cord injury (SCI) rats. An in vitro study demonstrated that MDSCs attenuated neuron apoptosis, and the expression of antioxidants was upregulated as well as the ratio of Bcl-2 and Bax in the MNT (MDSCs cocultured with injured neurons) group compared with the NT (injured neurons) group. Both LC3II/LC3I and β-catenin were enhanced in the MNT group, while XAV939 (a β-catenin inhibitor) decreased the expression of nuclear erythroid-related factor 2 (Nrf2) and LC3II/LC3I. Moreover, MDSCs became NSE- (neuron-specific enolase-) positive neuron-like cells with brain-derived neurotrophic factor (BDNF) treatment. The correlation analysis indicated that there was a significant relation between the level of BDNF and neuron injury. These findings suggest that MDSCs may protect the spinal cord from injury by inhibiting apoptosis and replacing injured neurons, and the increased BDNF and β-catenin could contribute to MDSCs' effects.

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“…Both a PEP-dependent protein kinase activity of M 2 -PYK [24,134,151,207,[219][220][221][222][223][224][225][226][227][228][229] and a translocation of dimeric M 2 PYK into the nucleus to act as a transcription factor [34,73,120,125,[230][231][232][233][234][235] have been proposed for M 2 PYK. The protein kinase activity appears to primarily be detected in the nucleus using nuclear proteins as substrates.…”

Section: Pyk In Non-canonical Role: Nuclear Translocation Of M 2 Pyk To Act As a Protein Kinasementioning

confidence: 99%

A critical review of the role of M2PYK in the Warburg effect

Harris

Fenton

2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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It is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M 2 PYK, the pyruvate kinase isozyme most commonly expressed in tumors. We remain skeptical. There continues to be a general lack of solid experimental evidence for the underlying idea that a bottle neck in aerobic glycolysis at the level of M 2 PYK results in an expanded pool of glycolytic intermediates (which are thought to serve as building blocks necessary for proliferation and growth of cancer cells). If a bottle neck at M 2 PYK exists, then the remarkable increase in lactate production by cancer cells is a paradox, particularly since a high percentage of the carbons of lactate originate from glucose. The finding that pyruvate kinase activity is invariantly increased rather than decreased in cancer undermines the logic of the M 2 PYK bottle neck, but is consistent with high lactate production. The "inactive" state of M 2 PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M 2 PYK. Although M 2 PYK clearly dissociates easier than other isozymes of pyruvate kinase, it is not clear that dissociation of the tetramer occurs in vivo when ligands are present that promote tetramer formation. Furthermore, it is also not clear whether the dissociated dimer retains any activity at all. A number of non-canonical functions for M 2 PYK have been proposed, all of which can be challenged by the finding that not all cancer cell types are dependent on M 2 PYK expression. Additional in-depth studies of the Warburg effect and specifically of the possible regulatory role of M 2 PYK in the Warburg effect are needed.

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Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

Cited by 39 publications

References 49 publications

PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells

PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells

The Neuroprotective Effects of Muscle-Derived Stem Cells via Brain-Derived Neurotrophic Factor in Spinal Cord Injury Model

A critical review of the role of M2PYK in the Warburg effect

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