Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity

Kai Hui Sun, Kuei Hua Chang, Sara Clawson, Soumitra Ghosh, Hamid Mirzaei, Fred Regnier, Kavita Shah

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Cyclin dependent kinase-5 (Cdk5) activity is deregulated in Alzheimer's disease (AD) and contributes to all three hallmarks: neurotoxic β-amyloid formation, neurofibrillary tangles, and neuronal death. However, the mechanism leading to Cdk5 deregulation remains controversial. Cdk5 deregulation in AD is usually linked to the formation of p25, a proteolysis product of Cdk5 activator p35, which leads to Cdk5 mislocalization and hyperactivation. A few studies have indeed shown increased p25 levels in AD brains; however, others have refuted this observation. These contradictory findings suggest that additional factors contribute to Cdk5 deregulation. This study identified glutathione-S-transferase pi 1 (GSTP1) as a novel Cdk5 regulatory protein. We demonstrate that it is a critical determinant of Cdk5 activity in human AD brains and various cancer and neuronal cells. Increased GSTP1 levels were consistently associated with reduced Cdk5 activity. GSTP1 directly inhibits Cdk5 by dislodging p25/p35, and indirectly by eliminating oxidative stress. Cdk5 promotes and is activated by oxidative stress, thereby engaging a feedback loop which ultimately leads to cell death. Not surprisingly, GSTP1 transduction conferred a high degree of neuroprotection under neurotoxic conditions. Given the critical role of oxidative stress in AD pathogenesis, an increase in GSTP1 level may be an alternative way to modulate Cdk5 signaling, eliminate oxidative stress, and prevent neurodegeneration.

Original languageEnglish (US)
Pages (from-to)902-914
Number of pages13
JournalJournal of Neurochemistry
Volume118
Issue number5
DOIs
StatePublished - Sep 2011

Fingerprint

Cyclin-Dependent Kinase 5
Glutathione Transferase
Phosphotransferases
Glutathione S-Transferase pi
Oxidative stress
Alzheimer Disease
Deregulation
Oxidative Stress
Brain
Proteolysis
Neurofibrillary Tangles
Cell death
Amyloid
Human Activities
Brain Neoplasms

Keywords

  • Alzheimer's disease
  • cancer
  • Cdk5
  • GSTP1
  • neurodegeneration
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Sun, K. H., Chang, K. H., Clawson, S., Ghosh, S., Mirzaei, H., Regnier, F., & Shah, K. (2011). Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. Journal of Neurochemistry, 118(5), 902-914. https://doi.org/10.1111/j.1471-4159.2011.07343.x

Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. / Sun, Kai Hui; Chang, Kuei Hua; Clawson, Sara; Ghosh, Soumitra; Mirzaei, Hamid; Regnier, Fred; Shah, Kavita.

In: Journal of Neurochemistry, Vol. 118, No. 5, 09.2011, p. 902-914.

Research output: Contribution to journalArticle

Sun, KH, Chang, KH, Clawson, S, Ghosh, S, Mirzaei, H, Regnier, F & Shah, K 2011, 'Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity', Journal of Neurochemistry, vol. 118, no. 5, pp. 902-914. https://doi.org/10.1111/j.1471-4159.2011.07343.x
Sun, Kai Hui ; Chang, Kuei Hua ; Clawson, Sara ; Ghosh, Soumitra ; Mirzaei, Hamid ; Regnier, Fred ; Shah, Kavita. / Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. In: Journal of Neurochemistry. 2011 ; Vol. 118, No. 5. pp. 902-914.
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