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Identification of JNK-dependent and -independent components of cerebellar granule neuron apoptosis.
J Neurochem. 2002 Nov; 83(4):992-1001.JN

Abstract

Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when switched to medium containing 5 mm potassium, a stimulus mimicking deafferentation. This cell death can be blocked by genetic deletion of Bax, a member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of macromolecular synthesis or expression of dominant-negative c-jun. These observations suggest that Bax activation is the result of c-jun target gene(s) up-regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell neuronal apoptosis in response to low potassium were investigated using CEP-1347 (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection of potassium-serum-deprived granule cells, but such neuroprotection was not long term. The incomplete protection was not due to incomplete blockade of the JNK signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA and protein were completely blocked by CEP-1347. Following potassium-serum deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347. Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition of caspases and MLKs has additive, not synergistic, effects on survival. A lack of synergism was also seen with the p38 inhibitor SB203580, indicating that the neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38 activation. Activation of the JNK signaling pathway seems to be a key event in granule cell apoptosis, but these neurons cannot survive long term in the absence of sustained PI3 kinase signaling.

Authors+Show Affiliations

Department of Molecular Biology, Washington University School of Medicine, St Louis, Missouri 63110, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12421372

Citation

Harris, Charles, et al. "Identification of JNK-dependent and -independent Components of Cerebellar Granule Neuron Apoptosis." Journal of Neurochemistry, vol. 83, no. 4, 2002, pp. 992-1001.
Harris C, Maroney AC, Johnson EM. Identification of JNK-dependent and -independent components of cerebellar granule neuron apoptosis. J Neurochem. 2002;83(4):992-1001.
Harris, C., Maroney, A. C., & Johnson, E. M. (2002). Identification of JNK-dependent and -independent components of cerebellar granule neuron apoptosis. Journal of Neurochemistry, 83(4), 992-1001.
Harris C, Maroney AC, Johnson EM. Identification of JNK-dependent and -independent Components of Cerebellar Granule Neuron Apoptosis. J Neurochem. 2002;83(4):992-1001. PubMed PMID: 12421372.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of JNK-dependent and -independent components of cerebellar granule neuron apoptosis. AU - Harris,Charles, AU - Maroney,Anna C, AU - Johnson,Eugene M,Jr PY - 2002/11/8/pubmed PY - 2002/12/27/medline PY - 2002/11/8/entrez SP - 992 EP - 1001 JF - Journal of neurochemistry JO - J Neurochem VL - 83 IS - 4 N2 - Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when switched to medium containing 5 mm potassium, a stimulus mimicking deafferentation. This cell death can be blocked by genetic deletion of Bax, a member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of macromolecular synthesis or expression of dominant-negative c-jun. These observations suggest that Bax activation is the result of c-jun target gene(s) up-regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell neuronal apoptosis in response to low potassium were investigated using CEP-1347 (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection of potassium-serum-deprived granule cells, but such neuroprotection was not long term. The incomplete protection was not due to incomplete blockade of the JNK signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA and protein were completely blocked by CEP-1347. Following potassium-serum deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347. Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition of caspases and MLKs has additive, not synergistic, effects on survival. A lack of synergism was also seen with the p38 inhibitor SB203580, indicating that the neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38 activation. Activation of the JNK signaling pathway seems to be a key event in granule cell apoptosis, but these neurons cannot survive long term in the absence of sustained PI3 kinase signaling. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/12421372/Identification_of_JNK_dependent_and__independent_components_of_cerebellar_granule_neuron_apoptosis_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=2002&volume=83&issue=4&spage=992 DB - PRIME DP - Unbound Medicine ER -