Age-associated changes in SAPK/JNK and p38 MAPK signaling in response to the generation of ROS by 3-nitropropionic acid

Ching Chyuan Hsieh, Judah I. Rosenblatt, John Papaconstantinou

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Mitochondrial dysfunction has been identified as a major source of oxidative stress in aged tissues. In this study we asked whether activities of components of the SAPK/JNK and p38 MAPK stress response signaling pathways are indicative of oxidative stress in aged mouse livers and whether these pathways are responsive to oxidative stress generated by 3-nitropropionic acid (3-NPA), an inhibitor of complex II (succinic dehydrogenase). We asked whether (a) aging affects the basal activity of the SAPK/JNK stress signaling pathway; (b) specific isoforms of JNK, i.e. 46 or 54 kDa JNKs are activated by 3-NPA; (c) aging affects the response of this signaling pathway to 3-NPA; (d) there is a cross pathway activation of JNK or p38 MAPK by upstream activators. Our studies have shown that although their protein pool levels are not altered, the basal JNK activities using c-Jun as substrate is elevated. Furthermore, in aged livers, JNK activity is induced to a greater extent and takes longer to recover from 3-NPA treatment. The activities of the upstream activators of JNKs, MAP kinase kinase (MKK) 4 and 7, are also elevated in livers of aged C57BL/6 male mice. These activator kinases, which are induced (phosphorylated) by 3-NPA in young livers, are not inducible by this inhibitor in aged livers. In fact, these proteins are highly phosphorylated in the control aged livers and are dephosphorylated in response to 3-NPA. Finally, we demonstrate for the first time that MKK7 serves as an upstream activator of p38 MAPK and that MKK3 and MKK6 activates 54 kDa JNK2 in aged liver. Our studies suggest that failure to respond to 3-NPA may be indicative of the susceptibility of aged tissue to oxidative stress, supporting our hypothesis that aged tissues (especially liver) develop a state of chronic stress even in the absence of a challenge.

Original languageEnglish (US)
Pages (from-to)733-746
Number of pages14
JournalMechanisms of Ageing and Development
Volume124
Issue number6
DOIs
StatePublished - Jun 1 2003

Fingerprint

p38 Mitogen-Activated Protein Kinases
Liver
Oxidative stress
Oxidative Stress
MAP Kinase Kinase 4
MAP Kinase Signaling System
Tissue
MAP Kinase Kinase 7
Aging of materials
Succinate Dehydrogenase
3-nitropropionic acid
Protein Isoforms
Proteins
Phosphotransferases
Chemical activation
Substrates

Keywords

  • 3-Nitropropionic acid
  • Aging
  • Liver
  • Mitogen activated protein kinases
  • Oxidative stress
  • p38 MAPK
  • SAPK/JNK

ASJC Scopus subject areas

  • Aging
  • Biochemistry
  • Developmental Biology
  • Developmental Neuroscience

Cite this

Age-associated changes in SAPK/JNK and p38 MAPK signaling in response to the generation of ROS by 3-nitropropionic acid. / Hsieh, Ching Chyuan; Rosenblatt, Judah I.; Papaconstantinou, John.

In: Mechanisms of Ageing and Development, Vol. 124, No. 6, 01.06.2003, p. 733-746.

Research output: Contribution to journalArticle

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AB - Mitochondrial dysfunction has been identified as a major source of oxidative stress in aged tissues. In this study we asked whether activities of components of the SAPK/JNK and p38 MAPK stress response signaling pathways are indicative of oxidative stress in aged mouse livers and whether these pathways are responsive to oxidative stress generated by 3-nitropropionic acid (3-NPA), an inhibitor of complex II (succinic dehydrogenase). We asked whether (a) aging affects the basal activity of the SAPK/JNK stress signaling pathway; (b) specific isoforms of JNK, i.e. 46 or 54 kDa JNKs are activated by 3-NPA; (c) aging affects the response of this signaling pathway to 3-NPA; (d) there is a cross pathway activation of JNK or p38 MAPK by upstream activators. Our studies have shown that although their protein pool levels are not altered, the basal JNK activities using c-Jun as substrate is elevated. Furthermore, in aged livers, JNK activity is induced to a greater extent and takes longer to recover from 3-NPA treatment. The activities of the upstream activators of JNKs, MAP kinase kinase (MKK) 4 and 7, are also elevated in livers of aged C57BL/6 male mice. These activator kinases, which are induced (phosphorylated) by 3-NPA in young livers, are not inducible by this inhibitor in aged livers. In fact, these proteins are highly phosphorylated in the control aged livers and are dephosphorylated in response to 3-NPA. Finally, we demonstrate for the first time that MKK7 serves as an upstream activator of p38 MAPK and that MKK3 and MKK6 activates 54 kDa JNK2 in aged liver. Our studies suggest that failure to respond to 3-NPA may be indicative of the susceptibility of aged tissue to oxidative stress, supporting our hypothesis that aged tissues (especially liver) develop a state of chronic stress even in the absence of a challenge.

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