Regulation of p53 by Activated Protein Kinase C-δ during Nitric Oxide-induced Dopaminergic Cell Death

Kim

Journal of Cell Science

et al. 2007

Self Cite

103

The p53 tumor suppressor protein is a key regulator of cellular functions including responses to numerous stress signals, and triggers apoptosis in many cell types, including neurons. The major mechanisms known to regulate p53 stabilization and activation include phosphorylation and ubiquitin ligase-mediated proteasomal degradation. Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, is most active in the central nervous system and plays a variety of roles in neuronal degeneration. Here, we demonstrate for the first time that Cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that Cdk5 phosphorylates p53 on Ser15, Ser33 and Ser46 in vitro, and that increased Cdk5 activity in the nucleus mediates these phosphorylation events in response to genotoxic and oxidative stresses. Cdk5 mediates disruption of the interaction between p53 and Hdm2 (also known as Mdm2), and prevents Hdm2-induced p53 ubiquitylation and downregulation. Cdk5 additionally enhances phosphorylation-dependent binding of the p300 coactivator, inducing acetylation of p53. Cdk5-stabilized p53 protein is transcriptionally active, resulting in the induction of pro-apoptotic genes and subsequent mitochondria-mediated apoptosis in response to genotoxic or oxidative stress. Collectively, these novel findings help define the mechanisms underlying neuronal apoptosis occurring as a result of Cdk5-mediated p53 stabilization and transcriptional activation.

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death

Kim

Journal of Cell Science

et al. 2007

Self Cite

103

“…to dopaminergic neuronal cell death [89] . Thus S-nitrosylation of key intracellular components can enhance the vulnerability of dopaminergic neurons to cell death either by activating them, as is the case with PKC-d, or by inactivating their protective functions, as seen with parkin, XIAP and peroxiredoxin-2.…”

Section: C-delta (Pkc-d) This In Turn Phosphorylates P53 Leadingmentioning

confidence: 99%

Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories

Doherty

2011

Neurosci. Bull.

Abstract:The cellular messenger nitric oxide (NO) has been linked to neurodegenerative disorders due to the increased expression of the enzymes that catalyze its synthesis in postmortem tissues derived from sufferers of these diseases. Nitrated proteins have also been detected in these samples, revealing that NO is biologically active in regions damaged during neurodegeneration. Modulation of NO levels has been reported not only in the neurons of the central nervous system, but also in the glial cells (microglia and astroglia) activated during the neuroinflammatory response. Neuroinflammation has been found in some neurodegenerative conditions, and inhibition of these neuroinflammatory signals has been shown to delay the progress of such disorders. Thus NO and the pathways triggering its release are emerging as an important research focus in the search for strategies to prevent, halt or cure neurodegenerative diseases.

Journal of Endocrinology

“…It has been suggested that PKC-d is involved in stabilizing p53 proteins (Lee et al 2006) and related to reactive oxygen species production (Domenicotti et al 2003), both of which would ultimately lead to apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

N-Acetylcysteine and α-cyano-4-hydroxycinnamic acid alter protein kinase C (PKC)-δ and PKC-ζ and diminish dysmorphogenesis in rat embryos cultured with high glucose in vitro

Gäreskog

Wentzel

2007

Malformations and growth disturbances are two-to threefold more common in infants of diabetic mothers than in offspring of non-diabetic pregnancy. Several suggestions have emerged to explain the reasons for diabetic embryopathy, including enhanced mitochondrial production of reactive oxygen species leading to altered activation of protein kinase C. This study aimed to evaluate the effect of a-cyano-4-hydroxycinnamic acid (CHC) and N-acetylcysteine (NAC) addition on morphology and activity of protein kinase C-d and protein kinase C-z in rat embryos exposed to a high glucose concentration in vitro. Day 9 embryos from normal rats were cultured in 10 or 30 mM glucose concentrations with or without supplementation of CHC, NAC, or protein kinase C inhibitors specific for protein kinase C-d and protein kinase C-z. Embryos were evaluated for malformations, crown rump length, and somite number. Protein kinase C-d and protein kinase C-z activities were estimated by western blot by separating membranous and cytosolic fractions of the embryo. We found increased malformations and growth retardation in embryos cultured in high versus low glucose concentrations. These abnormalities were diminished when CHC and NAC or specific protein kinase C-inhibitors were added to the culture medium. The activities of embryonic protein kinase C-d and protein kinase C-z were increased in the high glucose environment after 24-h culture, but were normalized by the addition of CHC and NAC as well as respective inhibitor to the culture medium. These findings suggest that mitochondrial overproduction of reactive oxygen species is involved in diabetic embryopathy. Furthermore, such overproduction may affect embryonic development, at least partly, by enhancing the activities of protein kinase C-d and protein kinase C-z.