Exp Mol Med.  2012 Mar;44(3):236-240. 10.3858/emm.2012.44.3.018.

p53 and DNA-dependent protein kinase catalytic subunit independently function in regulating actin damage-induced tetraploid G1 arrest

• Chae HD
• Kim SY
• Park SE
• Kim J
• Shin DY

• KMID: 1245266
• DOI: http://doi.org/10.3858/emm.2012.44.3.018

Abstract

We previously reported that the p53 tumor suppressor protein plays an essential role in the induction of tetraploid G1 arrest in response to perturbation of the actin cytoskeleton, termed actin damage. In this study, we investigated the role of p53, ataxia telangiectasia mutated protein (ATM), and catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in tetraploid G1 arrest induced by actin damage. Treatment with actin-damaging agents including pectenotoxin-2 (PTX-2) increases phosphorylation of Ser-15 and Ser-37 residues of p53, but not Ser-20 residue. Knockdown of ATM and DNA-PKcs do not affect p53 phosphorylation induced by actin damage. However, while ATM knockdown does not affect tetraploid G1 arrest, knockdown of DNA-PKcs not only perturbs tetraploid G1 arrest, but also results in formation of polyploidy and induction of apoptosis. These results indicate that DNA-PKcs is essential for the maintenance of actin damage induced-tetraploid G1 arrest in a p53-independent manner. Furthermore, actin damage-induced p53 expression is not observed in cells synchronized at G1/S of the cell cycle, implying that p53 induction is due to actin damage-induced tetraploidy rather than perturbation of actin cytoskeleton. Therefore, these results suggest that p53 and DNA-PKcs independently function for tetraploid G1 arrest and preventing polyploidy formation.

Keyword

actin cytoskeleton; ataxia telangiectasia mutated protein; DNA-activated protein kinase; pectenotoxin 2; tumor suppressor protein p53

MeSH Terms

Actins/*metabolism
Apoptosis
Catalytic Domain
Cell Cycle Proteins/genetics/*metabolism
Cell Line
Cell Line, Tumor
DNA-Activated Protein Kinase/chemistry/genetics/*metabolism
DNA-Binding Proteins/genetics/*metabolism
Furans/pharmacology
*G1 Phase
Gene Knockdown Techniques
Humans
Phosphorylation/drug effects
Protein-Serine-Threonine Kinases/genetics/*metabolism
Pyrans/pharmacology
Tumor Suppressor Protein p53/*metabolism
Tumor Suppressor Proteins/genetics/*metabolism