Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes.
Skin-derived fibroblasts from long-lived mutant mice, including the Snell dwarf mice and mice defective in growth hormone receptor (GHRKO mice), are resistant to death induced by oxidative stress or by UV light, but the molecular mechanism for their stress resistance is unknown. This study shows that phosphorylation of the stress-activated protein kinases ERK1/2 induced by peroxide, cadmium, or paraquat is attenuated in cells from these mice. Induction of ERK phosphorylation by UV light was not altered in the Snell dwarf cells, and neither JNK nor p38 kinase showed increased phosphorylation in response to any of the stresses tested. Surprisingly, stress-induced elevation of mRNA for certain immediate early genes (Egr-1 and Fos) was higher in Snell-derived cells than in control cells, despite the evidence of lower ERK phosphorylation. Thus cells from Snell dwarf mice differ from controls in two ways: (a) lower induction of ERK1/2 phosphorylation and (b) increased expression of some ERK-dependent immediate early genes. These alterations in kinase pathways may contribute to the resistance of these cells to lethal injury.
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
Liou Y
LY
Sun
Michael J
MJ
Steinbaugh
Michal M
MM
Masternak
Andrzej
A
Bartke
Richard A
RA
Miller
D000818:Animals; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008136:Longevity / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D010269:Paraquat / Q000494:pharmacology; D010766:Phosphorylation; D011986:Receptors, Somatotropin / Q000235:genetics*; D012867:Skin / Q000166:cytology / Q000201:enzymology*
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016761:Oncogene Proteins v-fos; D011986:Receptors, Somatotropin; D006861:Hydrogen Peroxide; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010269:Paraquat