Abstract
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.
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Abbreviations
- AO:
-
Acridine orange
- DMEM:
-
Dulbecco's modified Eagle's medium
- HBSS:
-
Hank's balanced salt solution
- HRP:
-
Horseradish peroxidase
- IL-6:
-
interleukin-6
- TRAP:
-
telomeric repeat amplification protocol
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Acknowledgements
This study was supported in part by grants from the Israel–USA Binational Science Foundation (BSF), the Israeli Science Foundation (ISF) and the Kadoori Foundation. VR is the incumbent of the Norman and Helen Asher Professorial Chair in Cancer Research at the Weizmann Institute.
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Matas, D., Milyavsky, M., Shats, I. et al. p53 is a regulator of macrophage differentiation. Cell Death Differ 11, 458–467 (2004). https://doi.org/10.1038/sj.cdd.4401379
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DOI: https://doi.org/10.1038/sj.cdd.4401379
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