p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner

Abstract

BackgroundThe tumor suppressor p53 is an important regulator that controls various cellular networks, including cell differentiation. Interestingly, some studies suggest that p53 facilitates cell differentiation, whereas others claim that it suppresses differentiation. Therefore, it is critical to evaluate whether this inconsistency represents an authentic differential p53 activity manifested in the various differentiation programs.Methodology/Principal FindingsTo clarify this important issue, we conducted a comparative study of several mesenchymal differentiation programs. The effects of p53 knockdown or enhanced activity were analyzed in mouse and human mesenchymal cells, representing various stages of several differentiation programs. We found that p53 down-regulated the expression of master differentiation-inducing transcription factors, thereby inhibiting osteogenic, adipogenic and smooth muscle differentiation of multiple mesenchymal cell types. In contrast, p53 is essential for skeletal muscle differentiation and osteogenic re-programming of skeletal muscle committed cells.ConclusionsThese comparative studies suggest that, depending on the specific cell type and the specific differentiation program, p53 may exert a positive or a negative effect, and thus can be referred as a “guardian of differentiation” at large.

MDM4 downregulates p53 transcriptional activity and response to stress during differentiation

“…3,4 We use our reporter system to show that basal p53 activity decreases as the ES cells differentiate and that differentiated ES cells are thus less sensitive to basal stress-induced p53 activation. Interestingly, p53 protein levels are higher in differentiating ES cells, suggesting that there is an Mdm2-and degradation-independent mechanism by which p53 activity is inhibited.…”

“…The transcription factor p53 has been shown to play a role in differentiation. 3,4 It is also crucial for the regulation of cell proliferation and for the maintenance of genomic integrity, which is essential in these ES cells in order to prevent tumorigenesis. Therefore, we sought to examine p53 activity and regulation in differentiating ES cells.…”

p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity

“…18 This multitask protein may either induce or suppress key differentiation factors depending on the specific cellular fate. 19 Although increasing evidence from in vitro and in vivo studies suggest that p53 exerts a negative effect on white adipogenic differentiation, 19,20,21 its role in brown fat differentiation has not been determined.…”

“…Our previous study demonstrated a negative regulatory role of p53 in white adipogenic differentiation of mouse embryonic fibroblasts (MEFs). 19 To corroborate the negative effect that p53 exerts on white adipogenic differentiation, we used additional mouse and human cell lines that represent various stages of adipogenic differentiation.…”

“…These data further validate the notion that p53 exerts an inhibitory effect on white adipogenic in MEFs as suggested before. 19 The 3T3-L1 pre-adipocyte cell line serves as a genuine model for differentiation of committed white pre-adipocytes into adipocytes. 23 Indeed these pre-adipocytes that carry wild-type (wt) p53 have been extensively used to explore the molecular regulation of terminal adipogenic differentiation.…”