Tags

Type your tag names separated by a space and hit enter

Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons.
J Neurosci 2002; 22(21):9287-97JN

Abstract

Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for their survival. However, the mechanism underlying the neuroprotective effects of IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by suppressing key elements of the intrinsic (mitochondrial) death pathway. IGF-I blocked activation of the executioner caspase-3 and the intrinsic initiator caspase-9 in primary cerebellar granule neurons deprived of serum and depolarizing potassium. IGF-I inhibited cytochrome c release from mitochondria and prevented its redistribution to neuronal processes. The effects of IGF-I on cytochrome c release were not mediated by blockade of the mitochondrial permeability transition pore, because IGF-I failed to inhibit mitochondrial swelling or depolarization. In contrast, IGF-I blocked induction of the BH3-only Bcl-2 family member, Bim (Bcl-2 interacting mediator of cell death), a mediator of Bax-dependent cytochrome c release. The suppression of Bim expression by IGF-I did not involve inhibition of the c-Jun transcription factor. Instead, IGF-I prevented activation of the forkhead family member, FKHRL1, another transcriptional regulator of Bim. Finally, adenoviral-mediated expression of dominant-negative AKT activated FKHRL1 and induced expression of Bim. These data suggest that IGF-I signaling via AKT promotes survival of cerebellar granule neurons by blocking the FKHRL1-dependent transcription of Bim, a principal effector of the intrinsic death-signaling cascade.

Authors+Show Affiliations

Department of Pharmacology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver, Colorado 80262, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

12417654

Citation

Linseman, Daniel A., et al. "Insulin-like Growth factor-I Blocks Bcl-2 Interacting Mediator of Cell Death (Bim) Induction and Intrinsic Death Signaling in Cerebellar Granule Neurons." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 22, no. 21, 2002, pp. 9287-97.
Linseman DA, Phelps RA, Bouchard RJ, et al. Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. J Neurosci. 2002;22(21):9287-97.
Linseman, D. A., Phelps, R. A., Bouchard, R. J., Le, S. S., Laessig, T. A., McClure, M. L., & Heidenreich, K. A. (2002). Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 22(21), pp. 9287-97.
Linseman DA, et al. Insulin-like Growth factor-I Blocks Bcl-2 Interacting Mediator of Cell Death (Bim) Induction and Intrinsic Death Signaling in Cerebellar Granule Neurons. J Neurosci. 2002 Nov 1;22(21):9287-97. PubMed PMID: 12417654.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. AU - Linseman,Daniel A, AU - Phelps,Reid A, AU - Bouchard,Ron J, AU - Le,Shoshona S, AU - Laessig,Tracey A, AU - McClure,Maria L, AU - Heidenreich,Kim A, PY - 2002/11/6/pubmed PY - 2002/11/26/medline PY - 2002/11/6/entrez SP - 9287 EP - 97 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 22 IS - 21 N2 - Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for their survival. However, the mechanism underlying the neuroprotective effects of IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by suppressing key elements of the intrinsic (mitochondrial) death pathway. IGF-I blocked activation of the executioner caspase-3 and the intrinsic initiator caspase-9 in primary cerebellar granule neurons deprived of serum and depolarizing potassium. IGF-I inhibited cytochrome c release from mitochondria and prevented its redistribution to neuronal processes. The effects of IGF-I on cytochrome c release were not mediated by blockade of the mitochondrial permeability transition pore, because IGF-I failed to inhibit mitochondrial swelling or depolarization. In contrast, IGF-I blocked induction of the BH3-only Bcl-2 family member, Bim (Bcl-2 interacting mediator of cell death), a mediator of Bax-dependent cytochrome c release. The suppression of Bim expression by IGF-I did not involve inhibition of the c-Jun transcription factor. Instead, IGF-I prevented activation of the forkhead family member, FKHRL1, another transcriptional regulator of Bim. Finally, adenoviral-mediated expression of dominant-negative AKT activated FKHRL1 and induced expression of Bim. These data suggest that IGF-I signaling via AKT promotes survival of cerebellar granule neurons by blocking the FKHRL1-dependent transcription of Bim, a principal effector of the intrinsic death-signaling cascade. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/12417654/Insulin_like_growth_factor_I_blocks_Bcl_2_interacting_mediator_of_cell_death__Bim__induction_and_intrinsic_death_signaling_in_cerebellar_granule_neurons_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=12417654 DB - PRIME DP - Unbound Medicine ER -