Heightened induction of proapoptotic signals in response to endoplasmic reticulum stress in primary fibroblasts from a mouse model of longevity

Amir A Sadighi Akha; James M Harper; Adam B Salmon; Bethany A Schroeder; Heather M Tyra; D Thomas Rutkowski; Richard A Miller

doi:10.1074/jbc.M111.220541

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Heightened induction of proapoptotic signals in response to endoplasmic reticulum stress in primary fibroblasts from a mouse model of longevity

Journal article

Open access

Peer reviewed

Heightened induction of proapoptotic signals in response to endoplasmic reticulum stress in primary fibroblasts from a mouse model of longevity

Amir A Sadighi Akha, James M Harper, Adam B Salmon, Bethany A Schroeder, Heather M Tyra, D Thomas Rutkowski and Richard A Miller

The Journal of biological chemistry, Vol.286(35), pp.30344-30351

09/02/2011

DOI: 10.1074/jbc.M111.220541

PMCID: PMC3162393

PMID: 21757703

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Abstract

Previous work from our laboratory has shown that primary fibroblasts from long-lived Snell dwarf mice display a higher sensitivity to the lethal effects of endoplasmic reticulum (ER) stressors, such as thapsigargin, than cells from normal mice. Here we show that thapsigargin induces higher expression of CHOP, enhanced cleavage of caspase-12, higher caspase-3 activity, and increased phosphorylation of c-JUN, all indicators of enhanced apoptosis, in dwarf fibroblasts. Dwarf and normal fibroblasts show no genotypic difference in up-regulating BiP, GRP94, and ERp72 proteins after exposure to thapsigargin. However, dwarf fibroblasts express lower basal levels of a number of putative XBP1 target genes including Armet, Edem1, Erdj3, p58(IPK) and Sec61a1, as well as Ire1α itself. Furthermore, when exposed to thapsigargin, dwarf fibroblasts display attenuated splicing of Xbp1, but similar phosphorylation of eIF2α, in comparison to normal fibroblasts. These data support the notion that IRE1/XBP1 signaling is set at a lower level in dwarf fibroblasts. Diminished Xbp1 splicing in dwarf-derived fibroblasts may tilt the balance between prosurvival and proapoptotic signals in favor of apoptosis, thereby leading to higher induction of proapoptotic signals in these cells and ultimately their increased sensitivity to ER stressors. These results, together with recent findings in Caenorhabditis elegans daf-2 mutants, point to a potential interplay between insulin/IGF-1 signals and unfolded protein response signaling.

Phosphorylation

Pituitary Gland - metabolism

Signal Transduction

Gene Expression Regulation

Caenorhabditis elegans Proteins - metabolism

Endoplasmic Reticulum - metabolism

Male

Mice, Transgenic

Longevity - genetics

Mice, Inbred C3H

Caenorhabditis elegans

Animals

Protein Denaturation

Female

Receptor, Insulin - metabolism

Mice

Mutation

Transcription Factor CHOP - metabolism

Apoptosis

Disease Models, Animal

Fibroblasts - metabolism

Details

Title: Subtitle: Heightened induction of proapoptotic signals in response to endoplasmic reticulum stress in primary fibroblasts from a mouse model of longevity
Creators: Amir A Sadighi Akha - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109. Electronic address: asadighi@umich.edu
James M Harper - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109
Adam B Salmon - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109
Bethany A Schroeder - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109
Heather M Tyra - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
D Thomas Rutkowski - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
Richard A Miller - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109; Geriatrics Center, University of Michigan Medical School, Ann Arbor, Michigan 48109; Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan 48105
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.286(35), pp.30344-30351
DOI: 10.1074/jbc.M111.220541
PMID: 21757703
PMCID: PMC3162393
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: R01 AG019899 / NIA NIH HHS P01 AG031736 / NIA NIH HHS DK084058 / NIDDK NIH HHS R01 DK084058 / NIDDK NIH HHS AG019899 / NIA NIH HHS R01 DK084058-03 / NIDDK NIH HHS AG031736 / NIA NIH HHS P30 AG024824 / NIA NIH HHS AG024824 / NIA NIH HHS
Language: English
Date published: 09/02/2011
Academic Unit: Anatomy and Cell Biology; Internal Medicine
Record Identifier: 9984094569502771

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