Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents.
Wild-type p53 is a tumor-suppressor gene that can induce cell death by apoptosis when expressed in myeloid leukemic and some other types of tumor cells. However, the question remained as to what extent wild-type p53 is a mediator of apoptosis in normal cells. We have used mice deficient in wild-type p53 to determine whether induction of apoptosis in hematopoietic cells from these p53 deficient mice is defective. We show here that bone marrow myeloid progenitor cells from p53-deficient mice are more resistant to induction of apoptosis when there was only a low concentration of the viability factors granulocyte-macrophage colony-stimulating factor; interleukins-1 alpha, -3, and -6; or stem cell factor; or when apoptosis was induced in these cells by irradiation or heat shock. The loss of one allele of wild-type p53 was sufficient for increased resistance. The higher resistance to apoptosis in p53-deficient mice was also found in irradiated thymocytes, but not in thymocytes treated with dexamethasone or in mature peritoneal granulocytes. The degree of resistance in irradiated myeloid progenitors and thymocytes showed a dosage effect of the number of wild-type p53 genes. The results show that wild-type p53 is involved in the induction of apoptosis by some agents in normal hematopoietic cells. Loss of wild-type p53 can, therefore, contribute to tumor development by decreasing cell death at low concentrations of viability factors and after exposure to a DNA-damaging agent. The results also show that there are wild-type p53-dependent and -independent pathways of normal cell apoptosis.
Lotem
J
J
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Sachs
L
L
D000818:Animals; D017209:Apoptosis; D003907:Dexamethasone / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects; D006358:Hot Temperature; D008297:Male; D051379:Mice; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000502:physiology
D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone