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

Kumiko Goi, Masatoshi Takagi, Satoshi Iwata, Domenico Delia, Minoru Asada, Rosangela Donghi, Yukiko Tsunematsu, Shinpei Nakazawa, Hiroshi Yamamoto, Jun Yokota, Kazuo Tamura, Yoshifumi Saeki, Joji Utsunomiya, Takashi Takahashi, Ryuzo Ueda, Chikashi Ishioka, Mariko Eguchi, Nanao Kamata, Shuki Mizutani

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

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 γ-irradiation was studied, these LCLs showed an abnormal G1 checkpoint associated with defective inhibition of cyclin F/cyclindependent kinase 2 activity in all eases 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.

Original languageEnglish
Pages (from-to)1895-1902
Number of pages8
JournalCancer Research
Volume57
Issue number10
Publication statusPublished - 1997 May 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation'. Together they form a unique fingerprint.

Cite this