In conclusion, p53 apparently plays a central role in normal cell differentiation and development. Data accumulated both from in vitro and in vivo models indicate that expression of p53 is directly involved in the induction of differentiation specific markers. Modulations in p53 expression interfere with the normal continuation of these processes. While for induction of apoptosis p53 has to be upregulated, in cell differentiation a direct correlation between upregulation of p53 and induction of cell differentiation or development are not always occurring. In some cell differentiation pathways p53 is induced, whereas in others it is down regulated. It is quite possible that these apparent opposite situations could result from various factors which are associated with the specific cell types, the stage of the cell in its differentiation pathway, or interactions with other oncogene-activated pathways (see Fig. 3). While in apoptosis p53 induces the expression of well defined apoptosis related genes, differentiation and development are more complex processes involving multiple pathways. Cell differentiation involve fine balance between cell replication and growth arrest. Stem cells, on the one hand, have the capacity to renew themselves through cell replication, while on the other hand can initiate differentiation through the generation of more mature daughter cells. We would like to suggest that either the level of p53 protein, or expression of specific p53 protein conformations, play a key role in determining whether stem cell renewal (proliferation) or differentiation (growth arrest) will occur. It is expected that 'activated' p53 will induce differentiation and maturation of the cells while 'non-activated' p53 will permit stem cell renewal. The various experimental models have clearly indicated that expression of mutant p53 forms interfere with various wild type p53-mediated activities. In several experimental models it was found that various p53 mutant protein forms block the induction of cell differentiation. This may suggest that mutant p53 can 'freeze' an undifferentiated cell at an early step on its terminal pathway towards maturation. The nature by which mutant p53 functions in the establishment of the transformed phenotype still remains unsolved. In agreement with the concept that p53 is the 'guardian of the genome', it is expected that such a role will also be maintained in cell differentiation and development. Clearly, in those differentiation pathways which involve DNA reshuffling and rearrangements, such a mechanism can be envisaged. It is quite possible that along processes, such as maturation of B and T cells of the immune response, or spermatogenesis, faulty DNA may accumulate. In these cases p53 may induce the DNA repair machinery to ensure the generation of mature cells with intact DNA. Alternatively, cells with high levels of irreparable damaged DNA are probably directed towards apoptosis or growth arrest. In differentiation models in which no DNA rearrangements were found to be involved, p53 may have yet other functions by which it may secure the generation of functionally intact differentiated cells. It is noteworthy, that most studies which examine p53-involvement in the DNA rearrangement processes were done in SCID cells. The investigation of the TCR and immunoglobulin rearrangement state in p53-null mice may help elucidating the role of p53 in these processes. In this respect it is worth mentioning that p53 null-mice develop a high incidence of T and B cell lymphomas. The overall function of wild type p53 appears to be associated with at least two major activities. One involving the suppressor activity of the wild type p53 that controls the out growth of tumors. The ability to induce p53-dependent apoptotic response in cells that accumulated high levels of faulty DNA, probably has no alternative pathways. Indeed, p53 knockout mice will develop a high incidence of tumors in adult life. The second p53- dependent activity, that is associated with normal development and differentiation, probably has alternative pathways that are achieved in the absence of p53. This may explain why p53 knockout mice still develop, and the relatively low incidence of developmental aberrations described in these mice. The possibility that a higher incidence of developmental aberrations do occur in p53 null mice, and still ignored, could be due to an early embryonic lethality. Taken together, the p53 tumor suppressor protein can be seen as a cellular 'master-switch', which does not only control the growth rate or the critical decision of the cell to commit suicide, but is also involved in the control of cell differentiation and development. Most likely, in order to direct the cell toward these various fates, p53 operates through different pathways, involving activation of different genes and proteins. Future studies should be aimed at elucidating the molecular mechanisms governing these critical decisions, and clarifying the role of p53 in the final outcome. Further identifications of p53-activated genes and proteins which interact with p53 during the differentiation process, as well as detailed examination of the p53 state and cellular localization, will illuminate these p53-mediated complex processes.
