Regulation of p53-mediated apoptosis and cell cycle arrest by Steel factor.
Activation of the p53 protein can lead to apoptosis and cell cycle arrest. In contrast, activation of the signalling pathway controlled by the Kit receptor tyrosine kinase prevents apoptosis and promotes cell division of a number of different cell types in vivo. We have investigated the consequences of activating the Kit signalling pathway by its ligand Steel factor on these opposing functions of the p53 protein in Friend erythroleukemia cells. A temperature-sensitive p53 allele (Val-135) was introduced into the Friend erythroleukemia cell line (DP-16) which lacks endogenous p53 expression. At 38.5 degrees C, the Val-135 protein maintains a mutant conformation and has no effect on cell growth. At 32 degrees C, the mutant protein assumes wild-type properties and induces these cells to arrest in G1, terminally differentiate, and die by apoptosis. We demonstrate that Steel factor inhibits p53-mediated apoptosis and differentiation but has no effect on p53-mediated G1/S cell cycle arrest. These results demonstrate that Steel factor functions as a cell survival factor in part through the suppression of differentiation and apoptosis induced by p53 and suggest that cell cycle arrest and apoptosis may be separable functions of p53.
Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
J L
JL
Abrahamson
J M
JM
Lee
A
A
Bernstein
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival; D005622:Friend murine leukemia virus; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute; D007942:Leukemia, Experimental; D051379:Mice; D008811:Mice, Inbred DBA; D017354:Point Mutation; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D014633:Valine
D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016159:Tumor Suppressor Protein p53; D014633:Valine