Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family

Malene Ambjørn; Johanne W Asmussen; Mats Lindstam; Kamil Gotfryd; Christian Jacobsen; Vladislav V Kiselyov; Søren K Moestrup; Milena Penkowa; Elisabeth Bock; Vladimir Berezin

doi:10.1111/j.1471-4159.2007.05036.x

Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family

Malene Ambjørn, Johanne W Asmussen, Mats Lindstam, Kamil Gotfryd, Christian Jacobsen, Vladislav V Kiselyov, Søren K Moestrup, Milena Penkowa, Elisabeth Bock, Vladimir Berezin

79 Citations (Scopus)

Abstract

Accumulating evidence suggests that metallothionein (MT)-I and -II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival-promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor-related protein-1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor-associated protein-1, an antagonist of the low-density lipoprotein receptor family, which also inhibited MT- and EmtinB-induced neurite outgrowth and survival. MT-mediated neurite outgrowth was furthermore inhibited by an anti-megalin serum. EmtinB-mediated inhibition of apoptosis occurred without a reduction of caspase-3 activity, but was associated with reduced expression of the pro-apoptotic B-cell leukemia/lymphoma-2 interacting member of cell death (Bim(S)). Finally, evidence is provided that MT and EmtinB activate extracellular signal-regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low-density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.

Original language	English
Journal	Journal of Neurochemistry
Volume	104
Issue number	1
Pages (from-to)	21-37
Number of pages	16
ISSN	0022-3042
DOIs	https://doi.org/10.1111/j.1471-4159.2007.05036.x
Publication status	Published - 2007

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10.1111/j.1471-4159.2007.05036.x

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Ambjørn, M., Asmussen, J. W., Lindstam, M., Gotfryd, K., Jacobsen, C., Kiselyov, V. V., Moestrup, S. K., Penkowa, M., Bock, E., & Berezin, V. (2007). Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family. Journal of Neurochemistry, 104(1), 21-37. https://doi.org/10.1111/j.1471-4159.2007.05036.x

Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family. / Ambjørn, Malene; Asmussen, Johanne W; Lindstam, Mats et al.

In: Journal of Neurochemistry, Vol. 104, No. 1, 2007, p. 21-37.

Research output: Contribution to journal › Journal article › Research › peer-review

Ambjørn, M, Asmussen, JW, Lindstam, M, Gotfryd, K, Jacobsen, C, Kiselyov, VV, Moestrup, SK, Penkowa, M, Bock, E & Berezin, V 2007, 'Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family', Journal of Neurochemistry, vol. 104, no. 1, pp. 21-37. https://doi.org/10.1111/j.1471-4159.2007.05036.x

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title = "Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family",

abstract = "Accumulating evidence suggests that metallothionein (MT)-I and -II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival-promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor-related protein-1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor-associated protein-1, an antagonist of the low-density lipoprotein receptor family, which also inhibited MT- and EmtinB-induced neurite outgrowth and survival. MT-mediated neurite outgrowth was furthermore inhibited by an anti-megalin serum. EmtinB-mediated inhibition of apoptosis occurred without a reduction of caspase-3 activity, but was associated with reduced expression of the pro-apoptotic B-cell leukemia/lymphoma-2 interacting member of cell death (Bim(S)). Finally, evidence is provided that MT and EmtinB activate extracellular signal-regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low-density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.",

author = "Malene Ambj{\o}rn and Asmussen, {Johanne W} and Mats Lindstam and Kamil Gotfryd and Christian Jacobsen and Kiselyov, {Vladislav V} and Moestrup, {S{\o}ren K} and Milena Penkowa and Elisabeth Bock and Vladimir Berezin",

note = "Keywords: Analysis of Variance; Animals; Animals, Newborn; Cell Differentiation; Cell Survival; Cells, Cultured; Cerebellum; Dose-Response Relationship, Drug; In Situ Nick-End Labeling; LDL-Receptor Related Protein 2; LDL-Receptor Related Protein-Associated Protein; Metallothionein; Models, Biological; Neurites; Neurons; Peptides; Protein Binding; Rats; Rats, Wistar; Receptors, LDL; Signal Transduction; Surface Plasmon Resonance",

year = "2007",

doi = "10.1111/j.1471-4159.2007.05036.x",

language = "English",

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pages = "21--37",

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T1 - Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family

AU - Ambjørn, Malene

AU - Asmussen, Johanne W

AU - Lindstam, Mats

AU - Gotfryd, Kamil

AU - Jacobsen, Christian

AU - Kiselyov, Vladislav V

AU - Moestrup, Søren K

AU - Penkowa, Milena

AU - Bock, Elisabeth

AU - Berezin, Vladimir

N1 - Keywords: Analysis of Variance; Animals; Animals, Newborn; Cell Differentiation; Cell Survival; Cells, Cultured; Cerebellum; Dose-Response Relationship, Drug; In Situ Nick-End Labeling; LDL-Receptor Related Protein 2; LDL-Receptor Related Protein-Associated Protein; Metallothionein; Models, Biological; Neurites; Neurons; Peptides; Protein Binding; Rats; Rats, Wistar; Receptors, LDL; Signal Transduction; Surface Plasmon Resonance

PY - 2007

Y1 - 2007

N2 - Accumulating evidence suggests that metallothionein (MT)-I and -II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival-promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor-related protein-1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor-associated protein-1, an antagonist of the low-density lipoprotein receptor family, which also inhibited MT- and EmtinB-induced neurite outgrowth and survival. MT-mediated neurite outgrowth was furthermore inhibited by an anti-megalin serum. EmtinB-mediated inhibition of apoptosis occurred without a reduction of caspase-3 activity, but was associated with reduced expression of the pro-apoptotic B-cell leukemia/lymphoma-2 interacting member of cell death (Bim(S)). Finally, evidence is provided that MT and EmtinB activate extracellular signal-regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low-density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.

AB - Accumulating evidence suggests that metallothionein (MT)-I and -II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival-promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor-related protein-1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor-associated protein-1, an antagonist of the low-density lipoprotein receptor family, which also inhibited MT- and EmtinB-induced neurite outgrowth and survival. MT-mediated neurite outgrowth was furthermore inhibited by an anti-megalin serum. EmtinB-mediated inhibition of apoptosis occurred without a reduction of caspase-3 activity, but was associated with reduced expression of the pro-apoptotic B-cell leukemia/lymphoma-2 interacting member of cell death (Bim(S)). Finally, evidence is provided that MT and EmtinB activate extracellular signal-regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low-density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.

U2 - 10.1111/j.1471-4159.2007.05036.x

DO - 10.1111/j.1471-4159.2007.05036.x

M3 - Journal article

C2 - 17986228

SN - 0022-3042

VL - 104

SP - 21

EP - 37

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

IS - 1

ER -

Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family

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