p53 is a regulator of macrophage differentiation.
While it is well accepted that p53 plays a role in apoptosis, less is known as to its involvement in cell differentiation. Here we show that wild-type p53 facilitates IL-6-dependent macrophage differentiation. Treatment of M1/2 cells expressing the temperature-sensitive p53 143 (Val to Ala) mutant, at the wild-type conformation, facilitated the appearance of mature macrophages that exhibited phagocytic activity. Enhancement of differentiation by the p53 143 (Val to Ala) in the wild-type conformation was coupled with the inhibition of apoptosis induction by this protein. In agreement with previous studies, we found that p53 levels were reduced during p53-dependent macrophage differentiation. This occurred when p53 levels before IL-6 stimuli were high. Interestingly, the p53 143 (Val to Ala) protein, at the mutant conformation, enhanced macrophage differentiation, as did the wild-type conformation, whereas the p53 273 (Arg to His) core mutant exerted an inhibitory effect on this pathway. The transcription-deficient p53 molecules, p53 (22-23) and p53 22,23,143, could not induce p53-dependent differentiation. Moreover, the p53 (22-23) protein inhibited the p53-independent differentiation pathway. Interestingly, the p53 (22-23) protein not only blocked IL-6-mediated differentiation, but also induced significant apoptotic cell death, upon IL-6 stimulation. Taken together, our data show that wild-type p53 enhances macrophage differentiation, while various p53 mutant types exert different effects on this differentiation pathway.
Matas
D
D
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Milyavsky
M
M
Shats
I
I
Nissim
L
L
Goldfinger
N
N
Rotter
V
V
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002999:Clone Cells; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D009154:Mutation; D022423:Myeloid Cells / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D015850:Interleukin-6; D016159:Tumor Suppressor Protein p53