Interference with p53 protein inhibits hematopoietic and muscle differentiation.

Abstract

Abstract. The involvement of p53 protein in cell differentiation has been recently suggested by some observations made with tumor cells and the correlation found between differentiation and increased levels of p53. However, the effect of p53 on differentiation is in apparent contrast with the normal development of p53-null mice. To test directly whether p53 has a function in cell differentiation, we interfered with the endogenous wt-p53 protein of nontransformed cells of two different murine histotypes: 32D myeloid progenitors, and C2C12 myoblasts. A drastic inhibition of terminal differentiation into granulocytes or myotubes, respectively, was observed upon expression of dominant-negative p53 proteins. This inhibition did not alter the cell cycle withdrawal typical of terminal differentiation, nor p21 (wAF1/cIP1) upregulation, indicating that interference with endogenous p53 directly affects cell differentiation, independently of the p53 activity on the cell cycle. We also found that the endogenous wt-p53 protein of C2C12 cells becomes transcriptionally active during myogenesis, and this activity is inhibited by p53 dominant-negative expression. Moreover, we found that p53 DNA-binding and transcriptional activities are both required to induce differentiation in p53-negative K562 cells. Taken together, these data strongly indicate that p53 is a regulator of cell differentiation and it exerts this role, at least in part, through its transcriptional activity.

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

“…When satellite cells were derived from p53 null mice, allowed to differentiate, and then exposed to MMS, DOXO or MND protection from cell killing was recorded after exposure to DOXO and MND, whereas no effect was observed after MMS treatment (Figure 8a). Muscle cells lacking p53 have a reduced ability to differentiate; 28 however, under our experimental conditions, we were able to achieve a differentiation efficiency above 80%, thus limiting the possible effects of contamination by proliferating cells. To confirm these results, the same experiment was conducted by silencing p53 in satellite cells by short hairpin RNA (shRNA; Figure 8b).…”

Increase of BCNU sensitivity by wt-p53 gene therapy in glioblastoma lines depends on the administration schedule

“…The plasmids PG 13 -CAT and MG 15 -CAT, 15 were generous gifts from B Vogelstein (John Hopkins Oncology Center, Baltimore, MD, USA). CAT assay was performed on cells 12 h after adriamycin (ADR) treatment (1 or 3 m) or 24 h after Ad-p53 infection.…”

“…12,13 Restoration of wtp53 function in different tumor types has been demonstrated to suppress the transformed phenotype by inducing growth arrest, apoptosis or cell differentiation. 14,15 Studies on glioblastomas have shown that overexpression of wt-p53 suppress cell growth, and induces apoptotic cell death in vitro and in vivo. [16][17][18][19] These findings have rendered p53 a potentially helpful target for gene therapy of brain tumors.…”

Muscle gets stressed? p53 represses and protects

“…10 In this issue, Yang et al propose a role of p53 in the activation of the myogenic differentiation checkpoint that relies on direct repression of myogenin-a MyoD downstream target gene, whose activation is required for myoblast progression toward terminal differentiation into multinucleated myotubes. 11,12 This finding is of particular interest, when considering that in unperturbed myoblasts p53 rather seems to contribute to muscle differentiation, 13,14 as it suggests that in myoblasts the activity of p53 is biased toward inhibiting differentiation by the DNA damage signaling. The authors first discovered the transcriptional repression of myogenin by p53 in the human rhabdomyosarcoma RD cell line.…”