REGγ deficiency promotes premature aging via the casein kinase 1 pathway

Lei Li, Dengpan Zhao, Haibin Wei, Liangfang Yao, Yongyan Dang, Ali Amjad, Jinjin Xu, Jiang Liu, Linjie Guo, Dongqing Li, Zhen Li, Di Zuo, Yuanyuan Zhang, Jian Liu, Shixia Huang, Caifeng Jia, Lu Wang, Ying Wang, Yifan Xie, Jian LuoBianhong Zhang, Honglin Luo, Lawrence A. Donehower, Robb Moses, Jianru Xiao, Bert W. O'Malley, Xiaotao Li

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ-/-tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ-/- MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.

Original languageEnglish (US)
Pages (from-to)11005-11010
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number27
DOIs
StatePublished - Jul 2 2013
Externally publishedYes

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Casein Kinase I
Premature Aging
Proto-Oncogene Proteins c-mdm2
Proteasome Endopeptidase Complex
Proteins
Cell Aging
Phenotype
Mammals
Antibodies

Keywords

  • Casein kinase 1
  • PA28γ

ASJC Scopus subject areas

  • General

Cite this

REGγ deficiency promotes premature aging via the casein kinase 1 pathway. / Li, Lei; Zhao, Dengpan; Wei, Haibin; Yao, Liangfang; Dang, Yongyan; Amjad, Ali; Xu, Jinjin; Liu, Jiang; Guo, Linjie; Li, Dongqing; Li, Zhen; Zuo, Di; Zhang, Yuanyuan; Liu, Jian; Huang, Shixia; Jia, Caifeng; Wang, Lu; Wang, Ying; Xie, Yifan; Luo, Jian; Zhang, Bianhong; Luo, Honglin; Donehower, Lawrence A.; Moses, Robb; Xiao, Jianru; O'Malley, Bert W.; Li, Xiaotao.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 27, 02.07.2013, p. 11005-11010.

Research output: Contribution to journalArticle

Li, L, Zhao, D, Wei, H, Yao, L, Dang, Y, Amjad, A, Xu, J, Liu, J, Guo, L, Li, D, Li, Z, Zuo, D, Zhang, Y, Liu, J, Huang, S, Jia, C, Wang, L, Wang, Y, Xie, Y, Luo, J, Zhang, B, Luo, H, Donehower, LA, Moses, R, Xiao, J, O'Malley, BW & Li, X 2013, 'REGγ deficiency promotes premature aging via the casein kinase 1 pathway', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 27, pp. 11005-11010. https://doi.org/10.1073/pnas.1308497110
Li, Lei ; Zhao, Dengpan ; Wei, Haibin ; Yao, Liangfang ; Dang, Yongyan ; Amjad, Ali ; Xu, Jinjin ; Liu, Jiang ; Guo, Linjie ; Li, Dongqing ; Li, Zhen ; Zuo, Di ; Zhang, Yuanyuan ; Liu, Jian ; Huang, Shixia ; Jia, Caifeng ; Wang, Lu ; Wang, Ying ; Xie, Yifan ; Luo, Jian ; Zhang, Bianhong ; Luo, Honglin ; Donehower, Lawrence A. ; Moses, Robb ; Xiao, Jianru ; O'Malley, Bert W. ; Li, Xiaotao. / REGγ deficiency promotes premature aging via the casein kinase 1 pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 27. pp. 11005-11010.
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T1 - REGγ deficiency promotes premature aging via the casein kinase 1 pathway

AU - Li, Lei

AU - Zhao, Dengpan

AU - Wei, Haibin

AU - Yao, Liangfang

AU - Dang, Yongyan

AU - Amjad, Ali

AU - Xu, Jinjin

AU - Liu, Jiang

AU - Guo, Linjie

AU - Li, Dongqing

AU - Li, Zhen

AU - Zuo, Di

AU - Zhang, Yuanyuan

AU - Liu, Jian

AU - Huang, Shixia

AU - Jia, Caifeng

AU - Wang, Lu

AU - Wang, Ying

AU - Xie, Yifan

AU - Luo, Jian

AU - Zhang, Bianhong

AU - Luo, Honglin

AU - Donehower, Lawrence A.

AU - Moses, Robb

AU - Xiao, Jianru

AU - O'Malley, Bert W.

AU - Li, Xiaotao

PY - 2013/7/2

Y1 - 2013/7/2

N2 - Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ-/-tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ-/- MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.

AB - Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ-/-tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ-/- MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.

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