CRM1 Protein-mediated Regulation of Nuclear Clusterin (nCLU), an Ionizing Radiation-stimulated, Bax-dependent Pro-death Factor

Leskov, Konstantin; Araki, Shinako; Lavik, John-Paul; Gómez, José Antonio Caride; Gama, Vivian; Gonos, Efstathios S.; Trougakos, Ioannis P.; Matsuyama, Shigemi; Boothman, David A.

doi:10.1074/jbc.m111.252957

Cited by 37 publications

(33 citation statements)

References 31 publications

(59 reference statements)

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“…28 CLU mRNA also encodes a nuclear form (≈50 kD) of CLU (nCLU) by alternative splicing, which is devoid of the signal peptide. 29 The sCLU is an antiapoptotic protein whereas nCLU is reported to be a proapoptotic factor. 23, 29 The CLU isoform identified as interactor of IAV NP in the yeast two-hybrid screen was sCLU and it has been referred as CLU in this report.…”

Section: Resultsmentioning

confidence: 99%

Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin

et al. 2013

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Apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death. The nucleoprotein (NP) of IAV is known to contribute to viral pathogenesis, but its role in virus-induced host cell death was hitherto unknown. We observed that NP contributes to IAV infection induced cell death and heterologous expression of NP alone can induce apoptosis in human airway epithelial cells. The apoptotic effect of IAV NP was significant when compared with other known proapoptotic proteins of IAV. The cell death induced by IAV NP was executed through the intrinsic apoptosis pathway. We screened host cellular factors for those that may be targeted by NP for inducing apoptosis and identified human antiapoptotic protein Clusterin (CLU) as a novel interacting partner. The interaction between IAV NP and CLU was highly conserved and mediated through β-chain of the CLU protein. Also CLU was found to interact specifically with IAV NP and not with any other known apoptosis modulatory protein of IAV. CLU prevents induction of the intrinsic apoptosis pathway by binding to Bax and inhibiting its movement into the mitochondria. We found that the expression of IAV NP reduced the association between CLU and Bax in mammalian cells. Further, we observed that CLU overexpression attenuated NP-induced cell death and had a negative effect on IAV replication. Collectively, these findings indicate a new function for IAV NP in inducing host cell death and suggest a role for the host antiapoptotic protein CLU in this process.

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Section: Resultsmentioning

confidence: 99%

Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin

et al. 2013

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“…It has been reported that apoptotic signals in human and rodent cells can induce the production of various CLU protein isoforms [16], most of which remain uncharacterized. Of these nonconventional isoforms, the most well-described variant refers to a stress-inducible nonglycosylated nucleocytosolic protein isoform of approximately 49 kDa (nCLU) that is encoded by an alternatively spliced mRNA of the CLU gene locus and reportedly exerts a cytostatic and proapoptotic function [26]. …”

Section: Apolipoprotein J/clusterin (Clu)mentioning

confidence: 99%

The Molecular Chaperone Apolipoprotein J/Clusterin as a Sensor of Oxidative Stress: Implications in Therapeutic Approaches - A Mini-Review

Trougakos

2013

Gerontology

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115

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Background: Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. Objective: The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. Conclusion: On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.

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“…Two types of clusterin, a conventional secreted isoform and a cytoplasmic and nuclear isoform, are thought to be involved in survival or cell death (Leskov et al 2011). Although clusterin expression in the nuclei is thought to be associated with apoptosis, our cell lines survive, despite clusterin expression in the nuclei.…”

Section: Sertoli Cell Lines From Adult Mouse Testismentioning

confidence: 86%

Establishment of adult mouse Sertoli cell lines by using the starvation method

Sato¹,

Yoshida²,

Nozawa³

et al. 2013

Reproduction

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Sertoli cells were isolated from the testes of 6-week-old mice and stable Sertoli cell lines with higher proliferation rates were subcloned after starvation of primary cultured cells. After two rounds of this subcloning, 33 subcloned lines were selected on the basis of their proliferation rates. In addition, these subclones were screened according to their phagocytic activity and the characteristics of mature Sertoli cells, such as the expression of androgen receptors (ARs) and progesterone receptors, by using western blotting and immunocytochemical analysis, in addition to their morphology and proliferation rates. After the third round of subcloning, 12 subclones were selected for the final selection using RT-PCR for identification of genes specifically expressed by various testicular cells. Three clones were selected that expressed Sertoli-cell-specific genes, i.e. stem cell factor, clusterin, AR, a-inhibin, transferrin, Wilms' tumour-1, Mü llerian inhibitory substance, sex-determining region Y-box 9, FSH receptor (Fshr) and occludin; however, these clones did not express globulin transcription factor 1, steroidogenic factor or androgen-binding protein. These clones also expressed growth and differentiation factors that act on germ cells, such as leukaemia inhibitory factor, transforming growth factor b1 and basic fibroblast growth factor 2, but did not express c-kit (specific for germ cells), LH receptor and 3b-hydroxyl-dehydrogenase (specific for Leydig cells). Immunocytochemical data confirmed the expression of clusterin in these clones. Furthermore, the Bromodeoxyuridine incorporation assay confirmed the proliferation activity of these clones through Fshr after treatment with FSH. These clones are considered to be valuable tools for the study of Sertoli cell-specific gene expression and function. Reproduction (2013) 145 505-516

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CRM1 Protein-mediated Regulation of Nuclear Clusterin (nCLU), an Ionizing Radiation-stimulated, Bax-dependent Pro-death Factor

Cited by 37 publications

References 31 publications

Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin

Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin

The Molecular Chaperone Apolipoprotein J/Clusterin as a Sensor of Oxidative Stress: Implications in Therapeutic Approaches - A Mini-Review

Establishment of adult mouse Sertoli cell lines by using the starvation method

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