p53 is a regulator of macrophage differentiation

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.

Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis

“…111 Similarly, although WT p53 enhances macrophage differentiation, various types of mutant p53 exert different effects on this differentiation pathway, either blocking or facilitating it. 112,113 Wang and coworkers 114 have used mice engineered to have an internal deletion mutation in exons 5-6 of TP53 specifically in neural stem and progenitor cells. They found that a majority of mice developed malignant brain tumors and that mutant p53 was detected in the tumor cells but not in normal cells.…”

p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome

“…153,154 It thus remains possible that closer examination of these and other tissues may uncover additional differentiation abnormalities associated with p53 deficiency. It is also possible that manifestations of p53 loss may only be evident in combination with alterations in other genes and then only in specific tissues.…”

NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiation

“…Transcriptional activity of p53 plays a direct role in embryonic stem cell differentiation by suppression of the Nanog gene [20], and can directly induce Xenopus homebox gene expression [21]. Involvement of p53 has also been shown in spermatogenesis [22], eye development [23] renal development [24], osteogenesis [25], immune development [26], lung development [27] and muscle differentiation [28]. Despite data supporting the transcriptional activity of p53 protein in differentiation, few genetic targets have been described and fewer still within a neuronal context.…”