Presenilin dependence of phospholipase C and protein kinase C signaling

Nodi Dehvari, Angel Cedazo-Minguez, Ola Isacsson, Tatjana Nilsson, Bengt Winblad, Helena Karlström, Eirikur Benedikz, Richard F Cowburn

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Presenilins (PSs) are involved in processing several proteins such as the amyloid precursor protein (APP), as well as in pathways for cell death and survival. We previously showed that some familial Alzheimer's disease PS mutations cause increased basal and acetylcholine muscarinic receptor-stimulated phospholipase C (PLC) activity which was gamma-secretase dependent. To further evaluate the dependence of PLC on PSs we measured PLC activity and the activation of variant protein kinase C (PKC) isoforms in mouse embryonic fibroblasts (MEFs) lacking either PS1, PS2, or both. PLC activity and PKCalpha and PKCgamma activations were significantly lower in PS1 and PS2 double knockout MEFs after PLC stimulation. Protein levels of PKCalpha and PKCgamma were lower in PS1 and PS2 double knockout MEFs. In contrast, PKCdelta levels were significantly elevated in PS1 and PS2 double knockout as well as in PS1 knockout MEFs. Also, PKCdelta levels were lowered after transfection of PS1 into PS1 knockout or PS double knockout MEFs. Using APP knockout MEFs we showed that the expression of PKCalpha, but not the other PKC isoforms is partially dependent on APP and can be regulated by APP intracellular domain (AICD). These results show that PLC and PKC activations are modulated by PS and also that PSs differentially regulate the expression of PKC isoforms by both APP/AICD-dependent and independent mechanisms.
OriginalsprogEngelsk
TidsskriftJournal of Neurochemistry
Vol/bind102
Udgave nummer3
Sider (fra-til)848-57
Antal sider10
ISSN0022-3042
DOI
StatusUdgivet - 2007

Fingeraftryk

Presenilins
Type C Phospholipases
Fibroblasts
Amyloid beta-Protein Precursor
Protein Kinase C
Protein Isoforms
Chemical activation
Amyloid Precursor Protein Secretases
Muscarinic Receptors
Cell death
Cell Survival
Alzheimer Disease
Proteins
Cell Death
Mutation
Processing

Citer dette

Dehvari, N., Cedazo-Minguez, A., Isacsson, O., Nilsson, T., Winblad, B., Karlström, H., ... Cowburn, R. F. (2007). Presenilin dependence of phospholipase C and protein kinase C signaling. Journal of Neurochemistry, 102(3), 848-57. https://doi.org/10.1111/j.1471-4159.2007.04571.x
Dehvari, Nodi ; Cedazo-Minguez, Angel ; Isacsson, Ola ; Nilsson, Tatjana ; Winblad, Bengt ; Karlström, Helena ; Benedikz, Eirikur ; Cowburn, Richard F. / Presenilin dependence of phospholipase C and protein kinase C signaling. I: Journal of Neurochemistry. 2007 ; Bind 102, Nr. 3. s. 848-57.
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title = "Presenilin dependence of phospholipase C and protein kinase C signaling",
abstract = "Presenilins (PSs) are involved in processing several proteins such as the amyloid precursor protein (APP), as well as in pathways for cell death and survival. We previously showed that some familial Alzheimer's disease PS mutations cause increased basal and acetylcholine muscarinic receptor-stimulated phospholipase C (PLC) activity which was gamma-secretase dependent. To further evaluate the dependence of PLC on PSs we measured PLC activity and the activation of variant protein kinase C (PKC) isoforms in mouse embryonic fibroblasts (MEFs) lacking either PS1, PS2, or both. PLC activity and PKCalpha and PKCgamma activations were significantly lower in PS1 and PS2 double knockout MEFs after PLC stimulation. Protein levels of PKCalpha and PKCgamma were lower in PS1 and PS2 double knockout MEFs. In contrast, PKCdelta levels were significantly elevated in PS1 and PS2 double knockout as well as in PS1 knockout MEFs. Also, PKCdelta levels were lowered after transfection of PS1 into PS1 knockout or PS double knockout MEFs. Using APP knockout MEFs we showed that the expression of PKCalpha, but not the other PKC isoforms is partially dependent on APP and can be regulated by APP intracellular domain (AICD). These results show that PLC and PKC activations are modulated by PS and also that PSs differentially regulate the expression of PKC isoforms by both APP/AICD-dependent and independent mechanisms.",
keywords = "Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Brain, Cells, Cultured, Down-Regulation, Fibroblasts, Gene Expression Regulation, Enzymologic, Isoenzymes, Mice, Mice, Knockout, Presenilin-1, Presenilin-2, Presenilins, Protein Kinase C, Protein Kinase C-alpha, Protein Kinase C-delta, Signal Transduction, Transfection, Type C Phospholipases",
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doi = "10.1111/j.1471-4159.2007.04571.x",
language = "English",
volume = "102",
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Dehvari, N, Cedazo-Minguez, A, Isacsson, O, Nilsson, T, Winblad, B, Karlström, H, Benedikz, E & Cowburn, RF 2007, 'Presenilin dependence of phospholipase C and protein kinase C signaling', Journal of Neurochemistry, bind 102, nr. 3, s. 848-57. https://doi.org/10.1111/j.1471-4159.2007.04571.x

Presenilin dependence of phospholipase C and protein kinase C signaling. / Dehvari, Nodi; Cedazo-Minguez, Angel; Isacsson, Ola; Nilsson, Tatjana; Winblad, Bengt; Karlström, Helena; Benedikz, Eirikur; Cowburn, Richard F.

I: Journal of Neurochemistry, Bind 102, Nr. 3, 2007, s. 848-57.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Presenilin dependence of phospholipase C and protein kinase C signaling

AU - Dehvari, Nodi

AU - Cedazo-Minguez, Angel

AU - Isacsson, Ola

AU - Nilsson, Tatjana

AU - Winblad, Bengt

AU - Karlström, Helena

AU - Benedikz, Eirikur

AU - Cowburn, Richard F

PY - 2007

Y1 - 2007

N2 - Presenilins (PSs) are involved in processing several proteins such as the amyloid precursor protein (APP), as well as in pathways for cell death and survival. We previously showed that some familial Alzheimer's disease PS mutations cause increased basal and acetylcholine muscarinic receptor-stimulated phospholipase C (PLC) activity which was gamma-secretase dependent. To further evaluate the dependence of PLC on PSs we measured PLC activity and the activation of variant protein kinase C (PKC) isoforms in mouse embryonic fibroblasts (MEFs) lacking either PS1, PS2, or both. PLC activity and PKCalpha and PKCgamma activations were significantly lower in PS1 and PS2 double knockout MEFs after PLC stimulation. Protein levels of PKCalpha and PKCgamma were lower in PS1 and PS2 double knockout MEFs. In contrast, PKCdelta levels were significantly elevated in PS1 and PS2 double knockout as well as in PS1 knockout MEFs. Also, PKCdelta levels were lowered after transfection of PS1 into PS1 knockout or PS double knockout MEFs. Using APP knockout MEFs we showed that the expression of PKCalpha, but not the other PKC isoforms is partially dependent on APP and can be regulated by APP intracellular domain (AICD). These results show that PLC and PKC activations are modulated by PS and also that PSs differentially regulate the expression of PKC isoforms by both APP/AICD-dependent and independent mechanisms.

AB - Presenilins (PSs) are involved in processing several proteins such as the amyloid precursor protein (APP), as well as in pathways for cell death and survival. We previously showed that some familial Alzheimer's disease PS mutations cause increased basal and acetylcholine muscarinic receptor-stimulated phospholipase C (PLC) activity which was gamma-secretase dependent. To further evaluate the dependence of PLC on PSs we measured PLC activity and the activation of variant protein kinase C (PKC) isoforms in mouse embryonic fibroblasts (MEFs) lacking either PS1, PS2, or both. PLC activity and PKCalpha and PKCgamma activations were significantly lower in PS1 and PS2 double knockout MEFs after PLC stimulation. Protein levels of PKCalpha and PKCgamma were lower in PS1 and PS2 double knockout MEFs. In contrast, PKCdelta levels were significantly elevated in PS1 and PS2 double knockout as well as in PS1 knockout MEFs. Also, PKCdelta levels were lowered after transfection of PS1 into PS1 knockout or PS double knockout MEFs. Using APP knockout MEFs we showed that the expression of PKCalpha, but not the other PKC isoforms is partially dependent on APP and can be regulated by APP intracellular domain (AICD). These results show that PLC and PKC activations are modulated by PS and also that PSs differentially regulate the expression of PKC isoforms by both APP/AICD-dependent and independent mechanisms.

KW - Alzheimer Disease

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Brain

KW - Cells, Cultured

KW - Down-Regulation

KW - Fibroblasts

KW - Gene Expression Regulation, Enzymologic

KW - Isoenzymes

KW - Mice

KW - Mice, Knockout

KW - Presenilin-1

KW - Presenilin-2

KW - Presenilins

KW - Protein Kinase C

KW - Protein Kinase C-alpha

KW - Protein Kinase C-delta

KW - Signal Transduction

KW - Transfection

KW - Type C Phospholipases

U2 - 10.1111/j.1471-4159.2007.04571.x

DO - 10.1111/j.1471-4159.2007.04571.x

M3 - Journal article

C2 - 17437536

VL - 102

SP - 848

EP - 857

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 3

ER -

Dehvari N, Cedazo-Minguez A, Isacsson O, Nilsson T, Winblad B, Karlström H et al. Presenilin dependence of phospholipase C and protein kinase C signaling. Journal of Neurochemistry. 2007;102(3):848-57. https://doi.org/10.1111/j.1471-4159.2007.04571.x