Redox control of G(1)/S cell cycle regulators during nitric oxide-mediated cell cycle arrest.

Abstract

Redox regulation of cell cycle progression during nitric oxide (NO) mediated cytostasis is not well-understood. In this study, we investigated the role of the intracellular antioxidant glutathione (GSH) in regulating specific signaling events that are associated with NO-mediated cell cycle arrest. Manipulation of intracellular GSH content through pharmacological inhibition of glutamate-cysteine ligase (GCL) indicated that GSH depletion potentiated nitrosative stress, DNA damage, phosphorylation of the tumor suppressor p53 (Ser-18) and upregulation of p21(cip1/waf1) upon NO stimulation. However, we found that neither overexpression of a dominant negative p53 nor pharmacological inhibition of p53 with cyclic pifithrin-alpha (cPFT-alpha) was sufficient to reverse NO-mediated cell cycle arrest or hypophosphorylation of retinoblastoma protein (Rb). We found that the decrease in cyclin D1 levels induced by NO was GSH-sensitive implying that the redox regulation of NO-mediated cytostasis was a multifaceted process and that both p53/p21(cip1/waf1) and p53 independent cyclin D1 pathways were involved. Together, our results demonstrate that GSH serves as an important component of cellular protective mechanisms against NO-derived nitrosative stress to regulate DNA damage checkpoint.

• Authors: Qi Lu, Frances L Jourd'Heuil, David Jourd'Heuil
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 212 Issue 3 Pg. 827-39 (Sep 2007) ISSN: 0021-9541 [Print] United States
• PMID: 17443686 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene
• Benzothiazoles
• Cdkn1a protein, mouse
• Cell Cycle Proteins
• Cyclin D
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Enzyme Inhibitors
• Nitric Oxide Donors
• Retinoblastoma Protein
• Triazenes
• Tumor Suppressor Protein p53
• Nitric Oxide
• Toluene
• Buthionine Sulfoximine
• pifithrin
• Glutamate-Cysteine Ligase
• Glutathione

Topics

• Animals
• Benzothiazoles (pharmacology)
• Buthionine Sulfoximine (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Proliferation (drug effects)
• Cyclin D
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclins (metabolism)
• DNA Damage
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (drug effects, enzymology, metabolism)
• G1 Phase (drug effects)
• Glutamate-Cysteine Ligase (antagonists & inhibitors, metabolism)
• Glutathione (metabolism)
• Mice
• NIH 3T3 Cells
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (pharmacology)
• Oxidation-Reduction
• Phosphorylation
• Retinoblastoma Protein (metabolism)
• S Phase (drug effects)
• Toluene (analogs & derivatives, pharmacology)
• Transfection
• Triazenes (pharmacology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)