Apoptosis or growth arrest: modulation of the cellular response to p53 by proliferative signals

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Abstract
Activation of the tumor suppressor p53 after genotoxic insults may result in two different responses: growth arrest or apoptosis. In this study, we analysed how mitogenic stimulation of primary mouse lymphocytes influences p53 signaling upon gamma-irradiation. We found that G(0) lymphocytes rapidly went into p53-dependent apoptosis, whereas stimulated lymphocytes went into a p53-dependent, p21-mediated growth arrest. The switch in p53 response upon stimulation did neither result from a switch in transcriptional activation of major p53 target genes, nor from the high level of p21 expressed in stimulated, irradiated cells. Growth stimulation, however, led to the upregulation of the antiapoptotic factors Bcl-x(L) and Bfl-1. In resting cells, p53 induced apoptosis after gamma-irradiation was accompanied by a breakdown of the mitochondrial membrane potential (psi(m)) that was counteracted by growth stimulation. We propose that growth stimulation intercepted p53 proapoptotic signaling at the level of mitochondrial integrity, most likely by upregulating the antiapoptotic factors Bcl-x(L) and Bfl-1. Upregulation of Bcl-x(L) and of Bfl-1 upon growth stimulation was mediated by the PKC-dependent activation of NF-kappaB. Consequently, blocking PKC activity restored apoptosis in stimulated, irradiated splenocytes. The inherent coupling of growth stimulation with antiapoptotic signaling in primary lymphocytes might provide hints as to how precancerous lymphocytes bypass the need for mutational inactivation of p53. Thus, our findings might explain the relatively low frequency of p53 mutations in lymphomas in comparison to other tumor entities.