DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation.
Cancer Res
; 57(10): 1895-902, 1997 May 15.
Article
en En
| MEDLINE
| ID: mdl-9157982
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 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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Genes p53
/
Síndrome de Li-Fraumeni
/
Apoptosis
/
Mutación de Línea Germinal
/
Quinasas CDC2-CDC28
Tipo de estudio:
Risk_factors_studies
Límite:
Adolescent
/
Adult
/
Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Cancer Res
Año:
1997
Tipo del documento:
Article
País de afiliación:
Japón