DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation

Cancer Res. 1997 May 15;57(10):1895-902.


Lymphoblastoid cell lines (LCLs) with heterozygous p53 mutations at residues 286A, 133R, 282W, 132E, and 213ter were established from five independent Li-Fraumeni syndrome families. When cell cycle regulation in response to gamma-irradiation was studied, these LCLs showed an abnormal G1 checkpoint associated with defective inhibition of cyclin E/cyclin-dependent kinase 2 activity in all cases except for 282W LCL, which showed a normal G1 checkpoint. On the other hand, the control of S-phase-G2 as determined by cyclin A/cyclin-dependent kinase 2 activity was defective in all these LCLs. The mitotic checkpoint was also defective in the two LCLs analyzed as either competent or incompetent for G1 arrest. When radiation-induced apoptosis, which requires wild-type p53 function under optimal conditions, was studied, all of these LCLs showed significant failure compared to normal LCLs. These findings indicate that although p53-dependent transactivation and G1-S-phase cell cycle control are variably dysregulated, the induction of apoptosis and control of the cell cycle at S-phase-G2 and the mitotic checkpoint in response to DNA-damaging agents are consistently dysregulated in heterozygous mutant LCLs. This suggests that these dysfunctions underlie, at least in part, the susceptibility of Li-Fraumeni syndrome families to cancer. Furthermore, the approach presented is a potentially useful method for studying individual carriers of different germ-line p53 mutations and different biological features.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • CDC2-CDC28 Kinases*
  • Cell Cycle / physiology
  • Cell Death / radiation effects
  • Cell Transformation, Viral
  • Child, Preschool
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / biosynthesis
  • Cyclins / metabolism
  • DNA Damage*
  • Disease Susceptibility
  • Female
  • Gene Expression
  • Genes, p53*
  • Germ-Line Mutation*
  • Herpesvirus 4, Human
  • Humans
  • Li-Fraumeni Syndrome / blood
  • Li-Fraumeni Syndrome / genetics*
  • Li-Fraumeni Syndrome / pathology*
  • Lymphocytes / cytology
  • Lymphocytes / physiology
  • Lymphocytes / radiation effects
  • Male
  • Phenotype
  • Protein Serine-Threonine Kinases / metabolism
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / physiology


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Tumor Suppressor Protein p53
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases