Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes

Sun, Liou Y.; Steinbaugh, Michael J.; Masternak, Michał M.; Bartke, Andrzej; Miller, Richard A.

doi:10.1016/j.freeradbiomed.2009.09.021

Cited by 34 publications

(31 citation statements)

References 41 publications

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“…Levels of these IEGs rise very rapidly in response to various forms of stress (24), and activation of PI3K-Akt and MAPK signaling pathways is involved in these responses (25,26). Our studies of Snell dwarf fibroblasts in culture (18) have shown, surprisingly, that dwarf cells showed stronger induction of ERK-dependent IEG mRNAs despite the relatively low levels of p-ERK induction. In these earlier studies, we also found that IEG activation was blocked in control and dwarf cells by MEK inhibition, showing that ERK phosphorylation is required for IEG activation.…”

Section: Stress-induced Expression Of Immediate Early Gene (Ieg) Famimentioning

confidence: 67%

“…The level of ERK phosphorylation induced by these stresses is, however, significantly lower in cells from Snell dwarf mice, suggesting defects in the pathways that sense cellular injury and lead to activation of the kinase MEK, responsible for phosphorylation of ERK (18). Paradoxically, despite the relatively low induction of ERK phosphorylation, cells from Snell dwarf mice show abnormally high levels of mRNA accumulation for a series of ERK-sensitive genes, including Egr-1, Fos, and Jun (18). Moreover, recently p38 phosphorylation was reported to occur in fibroblasts from Ames mice in response to the mitochondrial inhibitor rotenone, and cells from dwarf mice had an attenuated response compared with control cells (19).…”

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confidence: 99%

“…There are 3 major MAPK subfamilies, namely the extracellular signal-regulated protein kinases (ERK), the c-Jun N-terminal kinases (JNK), and p38 MAPK, and each set of kinases has been implicated in cell injury and disease pathogenesis (16,17). Exposure of primary skin-derived fibroblasts to peroxide, cadmium, or paraquat leads, within 60 min, to phosphorylation of the stress-activated kinases ERK1 and ERK2 (18). The level of ERK phosphorylation induced by these stresses is, however, significantly lower in cells from Snell dwarf mice, suggesting defects in the pathways that sense cellular injury and lead to activation of the kinase MEK, responsible for phosphorylation of ERK (18).…”

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confidence: 99%

“…Exposure of primary skin-derived fibroblasts to peroxide, cadmium, or paraquat leads, within 60 min, to phosphorylation of the stress-activated kinases ERK1 and ERK2 (18). The level of ERK phosphorylation induced by these stresses is, however, significantly lower in cells from Snell dwarf mice, suggesting defects in the pathways that sense cellular injury and lead to activation of the kinase MEK, responsible for phosphorylation of ERK (18). Paradoxically, despite the relatively low induction of ERK phosphorylation, cells from Snell dwarf mice show abnormally high levels of mRNA accumulation for a series of ERK-sensitive genes, including Egr-1, Fos, and Jun (18).…”

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Hepatic response to oxidative injury in long‐lived Ames dwarf mice

et al. 2010

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Multiple stress resistance pathways were evaluated in the liver of Ames dwarf mice before and after exposure to the oxidative toxin diquat, seeking clues to the exceptional longevity conferred by this mutation. Before diquat treatment, Ames dwarf mice, compared with nonmutant littermate controls, had 2- to 6-fold higher levels of expression of mRNAs for immediate early genes and 2- to 5-fold higher levels of mRNAs for genes dependent on the transcription factor Nrf2. Diquat led to a 2-fold increase in phosphorylation of the stress kinase ERK in control (but not Ames dwarf) mice and to a 50% increase in phosphorylation of the kinase JNK2 in Ames dwarf (but not control) mice. Diquat induction of Nrf2 protein was higher in dwarf mice than in controls. Of 6 Nrf2-responsive genes evaluated, 4 (HMOX, NQO-1, MT-1, and MT-2) remained 2- to 10-fold lower in control than in dwarf liver after diquat, and the other 2 (GCLM and TXNRD) reached levels already seen in dwarf liver at baseline. Thus, livers of Ames dwarf mice differ systematically from controls in multiple stress resistance pathways before and after exposure to diquat, suggesting mechanisms for stress resistance and extended longevity in Ames dwarf mice.

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Section: Stress-induced Expression Of Immediate Early Gene (Ieg) Famimentioning

confidence: 67%

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confidence: 99%

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confidence: 99%

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Hepatic response to oxidative injury in long‐lived Ames dwarf mice

et al. 2010

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“…Hence, we hypothesized that fibroblasts from longlived birds would also be more resistant to stress than cells from short-lived birds. In the case of mice, cells from long-lived stocks differ from control cells in DNA repair capacity (Salmon et al, 2008b), and signaling through the Nrf2 (Leiser and Miller, 2009) and MAP kinase pathways (Sun et al, 2009), although the extent to which these differences affect cells in vivo is unclear, as is whether differential signaling through these pathways is conserved among long-lived species.…”

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confidence: 99%

Fibroblasts from long-lived bird species are resistant to multiple forms of stress

Harper

Wang

Gałecki

et al. 2011

Journal of Experimental Biology

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number of mouse-sized passerines (e.g. swallows and sparrows) can live as much as three to four times longer than mice. Birds achieve this remarkable longevity despite their exceptionally high metabolic rate coupled with the high energetic demands of .37, P<0.01). They did not differ in their resistance to UV radiation, or to thapsigargin or tunicamycin, inducers of the unfolded protein response. These results were largely consistent even after accounting for the influence of body mass and phylogeny. Cell lines from longer-lived bird species also proliferate more rapidly than cells from short-lived birds, although there was no relationship between proliferation and stress resistance. Finally, avian fibroblasts were significantly more resistant than rodent fibroblasts to each of the tested stressors. These results support the idea that cellular resistance to injury may be an important contributor to the evolution of slow aging and long lifespan among bird species, and may contribute to the relatively long lifespan of birds compared with rodents of the same body size. Supplementary material available online at

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Key regulators of mitochondrial biogenesis are increased in kidneys of growth hormone receptor knockout (GHRKO) mice

Gesing¹,

Bartke

Wang

et al. 2011

Cell Biochemistry & Function

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The growth hormone (GH) receptor knockout mice (GHRKO) are remarkably long-lived and highly insulin sensitive. Alterations in mitochondrial biogenesis are associated with aging and various metabolic derangements. We have previously demonstrated increased gene expression of key regulators of mitochondriogenesis in kidneys, hearts and skeletal muscles of GHRKO mice. The aim of the present study was to quantify the protein levels of the following regulators of mitochondriogenesis: peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), AMP-activated protein kinase α (AMPKα), phospho-AMPKα (p-AMPKα), sirtuin-3 (SIRT-3), endothelial nitric oxide synthase (eNOS), phospho-eNOS (p-eNOS), nuclear respiratory factor-1 (NRF-1) and mitofusin-2 (MFN-2) in skeletal muscles and kidneys of GHRKOs in comparison to normal mice. We were also interested in the effects of calorie restriction (CR) and visceral fat removal (VFR) on these parameters. Both CR and VFR improve insulin sensitivity and can extend lifespan. Results: The renal levels of PGC-1α, AMPKα, p-AMPKα, SIRT-3, eNOS, p-eNOS and MFN-2 were increased in GHRKOs. In the GHRKO skeletal muscles, only MFN-2 was increased. Levels of the examined proteins were not affected by CR (except for PGC-1α and p-eNOS in skeletal muscles) or VFR. Conclusion: GHRKO mice have increased renal protein levels of key regulators of mitochondriogenesis and this may contribute to increased longevity of these knockouts.

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Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes

Cited by 34 publications

References 41 publications

Hepatic response to oxidative injury in long‐lived Ames dwarf mice

Hepatic response to oxidative injury in long‐lived Ames dwarf mice

Fibroblasts from long-lived bird species are resistant to multiple forms of stress

Key regulators of mitochondrial biogenesis are increased in kidneys of growth hormone receptor knockout (GHRKO) mice

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