GSK3β-Dependent Phosphorylation of the αNAC Coactivator Regulates Its Nuclear Translocation and Proteasome-Mediated Degradation

Quélo, Isabelle; Akhouayri, Omar; Prud’homme, Josée; St‐Arnaud, René

doi:10.1021/bi036256+

Cited by 37 publications

(41 citation statements)

References 47 publications

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“…45 Therefore, another possible and specific mediator of aNAC degradation could be GSK-3b; aNAC is a target for degradation by the 26S proteasome, which is regulated by GSK3b-dependent phosphorylation. 28 Indeed, this study demonstrated that hypoxic stress was associated with dephosphorylation of GSK-3b and that the inhibition of GSK-3b by lithium ions prevented dephosphorylation of GSK-3b and downregulation of aNAC, which rescued the hypoxic cells from apoptosis ( Figure 6). GSK-3b phosphorylates proteins at serine or threonine residues that are located 4 amino acids N-terminal to another phosphoserine (priming phosphorylation), which is introduced by other protein kinases.…”

Section: Discussionmentioning

confidence: 71%

“…27 A recent study has shown that GSK-3b can phosphorylate aNAC and that the GSK-3b-dependent phosphorylation of aNAC stimulated aNAC degradation. 28 Therefore, we tested the possibility that the prevention of aNAC degradation by the inhibition of GSK-3b might rescue the hypoxic cells from apoptosis. We found that GSK-3b activation and aNAC degradation coincided in hypoxic SK-N-SH cells (Figure 6a).…”

Section: Resultsmentioning

confidence: 99%

“…46 However, at present, the aNAC protein does not fulfill all the requirements as a physiological substrate for GSK-3b. 27,28 Further studies are required for determining whether aNAC is a target of GSK-3b. Notwithstanding these facts, the phosphorylation-dependent aNAC downregulation and the subsequent induction of ER stress are intriguing with regard to understanding the mechanisms for the initiation of ER stress-induced apoptosis in hypoxia.…”

Section: Discussionmentioning

confidence: 99%

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αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Hotokezaka

Leyen

et al. 2009

Cell Death Differ

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Accumulation of unfolded proteins triggers endoplasmic reticulum (ER) stress and is considered a part of the cellular responses to hypoxia. The nascent polypeptide-associated complex (NAC) participates in the proper maturation of newly synthesized proteins. However, thus far, there have been no comprehensive studies on NAC involvement in hypoxic stress. Here, we show that hypoxia activates glycogen synthase kinase-3b (GSK-3b) and that the activated GSK-3b destabilizes aNAC with the subsequent apoptosis of the cell. Hypoxia of various cell types and the mouse ischemic brain was associated with rapid downregulation of aNAC and ER stress responses involving PERK, ATF4, c-taxilin, elF2a, Bip, and CHOP. Depletion of aNAC by RNA interference specifically activated ER stress responses and caused mitochondrial dysfunction, which resulted in apoptosis through caspase activation. Interestingly, we found that the hypoxic conditions activated GSK-3b, and that GSK-3b inhibition prevented aNAC protein downregulation in hypoxic cells and rescued the cells from apoptosis. In addition, aNAC overexpression increased the viability of hypoxic cells. Taken together, these results suggest that aNAC degradation triggers ER stress responses and initiates apoptotic processes in hypoxic cells, and that GSK-3b may participate upstream in this mechanism.

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Section: Discussionmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Hotokezaka

Leyen

et al. 2009

Cell Death Differ

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“…In addition to acting as a protein translation chaperone, NACA also functions as a transcriptional coactivator in conjunction with an acidic activator (28,29). NACA may be phosphorylated by several kinases in vitro and its function as a transcriptional coactivator is regulated by phosphorylation change (30,31). Findings of the present study have shown that the phosphorylation level of NACA was not altered in the inflammatory pain model compared to the control, but that EA treatment increased the phosphorylation level.…”

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confidence: 44%

Phosphoproteomic analysis of electroacupuncture analgesia in an inflammatory pain rat model

Lee

Kim

et al. 2012

Mol Med Report

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Abstract. The phosphorylation changes of nociceptive signaling proteins in the spinal cord dorsal horn (SCDH) are important in creating exaggerated pain following peripheral inflammation. Electroacupuncture (EA) has been widely used to relieve acute and chronic inflammatory pain in human and experimental pain models. In the present study, we performed a phosphoproteomic analysis to investigate whether EA alters protein phosphorylation in SCDH to attenuate pain development. Inflammatory hyperalgesia was induced by intraplantar injection of complete Freund's adjuvant (CFA) into the rat hind paw. EA treatment at ST36 and SP6 acupoints alleviated thermal hyperalgesia of the CFA-induced inflammatory pain model rats. The SCDH proteins from the control, inflammatory pain model and EA treatment rats were separated by 2-dimensional gel electrophoresis and the alterations in phosphoproteins were detected by Pro-Q Diamond staining. Eight proteins were differentially phosphorylated following EA treatment in the inflammatory pain model. Aldolase C, nascent polypeptide-associated complex α, stress-induced phosphoprotein 1 and heat shock protein 90 were identified as phosphoproteins whose expression was increased, whereas GDP dissociation inhibitor 1, thiamine triphosphatase, phosphoglycerate kinase 1 and 14-3-3 γ were phosphoproteins whose expression was decreased. This is the first phosphoproteomic screening study to elucidate the working mechanisms of EA analgesia. The results suggest that the regulation of cellular pathways in which the identified proteins are involved may be associated with an EA analgesic mechanism. IntroductionPeripheral inflammation frequently leads to the development of chronic pain, which is a leading cause of disability globally. In inflammatory pain, peripheral stimuli activate primary afferent neurons and are transmitted to secondary sensory neurons in the spinal cord dorsal horn (SCDH). Persistent noxious stimuli increase the excitability of secondary neurons in the SCDH and decrease the pain threshold. Early studies attributed this central sensitization to the facilitated synaptic transmission of nociceptive signals in the SCDH (1,2). Various signaling molecules such as glutamate receptors, protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), Ca 2+ -/calmodulin-dependent kinase II (CaMKII) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38 and c-jun N-terminal kinase (JNK), have been shown to be involved in altered nociceptive processing in the SCDH (3-5). Activation of these molecules is capable of inducing signaling cascades that lead to the subsequent expression of pain-associated genes such as prodynorphin, neurokinin-1 (NK-1) and cyclooxygenase-2 (COX-2) (6,7).Acupuncture, a traditional therapeutic method in oriental medicine, has long been clinically used to relieve pain. In particular, electroacupuncture (EA), where electrical stimulation is applied to acupuncture needles, is widely used in clinical an...

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“…Papachristou et al showed that αNAC was expressed in osteosarcoma, but not in normal bone, and was expressed more strongly in high grade tumors compared with low grade tumors on immunohistochemical analysis (31). αNAC is involved in a coactivator potentiating c-Jun-mediated transcription process (20,33,34). Oya et al have reported that activation of C-Jun is acquired during aberrant proliferation of RCC (30).…”

Section: Referencesmentioning

confidence: 99%

Increased alpha-taxilin protein expression is associated with the metastatic and invasive potential of renal cell cancer

et al. 2011

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Intracellular vesicle trafficking is the principal transportation system in eukaryotic cells, and is considered to be involved in a variety of processes related to cell proliferation. A protein named alpha-taxilin has been identified as a binding partner of the syntaxin family, which coordinates intracellular vesicle trafficking. To clarify the role of alpha-taxilin in renal cell carcinoma (RCC), we investigated alpha-taxilin protein expression in clear cell RCC tissues. We analyzed alphataxilin protein in matched sets of tumor and non-tumor tissues from the surgical specimens of 52 Japanese RCC patients by Western blotting. We also studied the relation between alpha-taxilin protein expression in tumor tissues and various clinicopathological features. The alpha-taxilin protein level was higher in tumor tissues than in non-tumor tissues (P < 0.05). Increased expression of alpha-taxilin protein in primary tumors was related to local invasion (P < 0.001), pathological vessel invasion (P < 0.001), and metastasis (P < 0.0001). Kaplan-Meier plots of survival for patients with low versus high alpha-taxilin expression revealed that high expression in tumor tissues was associated with shorter overall survival in all patients (P < 0.05) and with shorter disease-free survival in patients without metastasis (P < 0.01). These findings suggest that alpha-taxilin influences the metastatic and invasive potential of RCC.Intracellular vesicle trafficking is the principal transportation system in eukaryotic cells, and vesicle trafficking is thought to be involved in various processes related to cell proliferation. Abnormal proliferation is the hallmark of cancer. Recently, a protein named alpha (α)-taxilin was identified as a binding partner of the syntaxin family, which is involved in the coordination of intracellular vesicle trafficking (26). The taxilin family has at least three members-α-, beta (β)-, and gamma (γ)-taxilin-and α-taxilin possesses an extremely long coiled-coil region and interacts with syntaxin family members localized on the plasma membrane, but not with those localized on intracellular organelles (26, 28). There is evidence that the taxilin family is involved in the transfer of vesicles delivered to the plasma membrane (26, 28). However, the precise influence of the taxilin family on the functions of the syntaxin family remains to be fully elucidated, and the actual role of α-taxilin in intracellular vesicle trafficking is also unknown. In addition to providing information about the molecular mechanisms involved, examination of the physiological and pathophysiological functions of taxilin should improve our understanding about the role of this family of proteins. We recently reported that α-taxilin protein is significantly upregulated in proliferating neural stem cells during embryonic development in the rat (37). In addition, Oba-Shinjo et al. recently reported that

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GSK3β-Dependent Phosphorylation of the αNAC Coactivator Regulates Its Nuclear Translocation and Proteasome-Mediated Degradation

Cited by 37 publications

References 47 publications

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Phosphoproteomic analysis of electroacupuncture analgesia in an inflammatory pain rat model

Increased alpha-taxilin protein expression is associated with the metastatic and invasive potential of renal cell cancer

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