Anti-inflammatory activity of SMP30 modulates NF-κB through protein tyrosine kinase/phosphatase balance.
Recent studies on senescence marker protein-30 (SMP30) have shown that it has an important functional role in the aging process, but its precise participation in cellular works has not been fully determined. We hypothesize that SMP30 plays crucial roles in signaling processes by modulating the balance of protein tyrosine kinase (PTK)/protein tyrosine phosphatase (PTP) and in activating proinflammatory NF-κB. An experimental paradigm of gain and loss of SMP30 function was established using SMP30-overexpressed YPEN-1 cells (herein referred to as "SMP30(+) cells") and SMP30 (Y/-) knockout mouse kidneys. The resulting data show that SMP30 expression suppressed oxidative stress-induced PTK/PTP dysregulation and PP1/2A inactivation in SMP30(+) cells, leading to the suppression of NF-κB activation. In the kidneys of SMP30 (Y/-) mice, SMP30 deficiency was found to induce NF-κB activation via the upstream signaling of NIK/IKK and MAPKs and to upregulate downstream NF-κB-responsive gene expression. In this study, we also demonstrate for the first time that SMP30 deficiency induced PTK activity in SMP30 (Y/-) kidneys, thereby significantly increasing the tyrosine phosphorylation of a catalytic subunit of PP2A (PP2Ac-Tyr307). Based on these findings, we propose that SMP30 involves NF-κB regulation through the PTK/PTP balance and that the age-related decrease of SMP30 causes NF-κB activation, which contributes to an exacerbation of the inflammatory process during aging.


CONCLUSIONS
SMP30-deficient mice induced a shorter lifespan and redox changes. Overexpression of SMP30 prevented oxidative stress insults. The depletion of SMP30 increased redox-related PTK/PTP imbalance and PP1/PP2A inactivation. The depletion of SMP30 caused an elevation of NF-κB-responsive inflammatory markers. SMP30 may be a potent inhibitory protein against oxidative stress and chronic inflammation.
Korea Institute of Toxicology, 141 Gajungro, Yuseong-gu, Daejeon, 305-343, Republic of Korea.
Kyung Jin
KJ
Jung
Eun Kyeong
EK
Lee
Su Jin
SJ
Kim
Chang Woo
CW
Song
Naoki
N
Maruyama
Akihito
A
Ishigami
Nam Deuk
ND
Kim
Dong-Soon
DS
Im
Byung Pal
BP
Yu
Hae Young
HY
Chung
D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C513324:Rgn protein, mouse; D011505:Protein-Tyrosine Kinases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2