Crosstalk between p53 and nuclear factor-κB systems: pro- and anti-apoptotic functions of NF-κB

Nuclear factors p53 and NF-kappaB control many physiological processes including cell cycle arrest, DNA repair, apoptosis, death, innate and adaptive immune responses, and inflammation. There are numerous pathways linking these systems and there is a bulk of evidence for cooperation as well as for antagonisms between p53 and NF-kappaB. In this theoretical study, the authors use earlier models of p53 and NF-kappaB systems and construct a crosstalk model of p53-NF-kappaB network in order to explore the consequences of the two-way coupling, in which NF-kappaB upregulates the transcription of p53, whereas in turn p53 attenuates transcription of NF-kappaB inhibitors IkappaBalpha and A20. We consider a number of protocols in which cells are stimulated by tumour necrosis factor-alpha (TNFalpha) (that activates NF-kappaB pathway) and/or gamma irradiation (that activates p53 pathway). The authors demonstrate that NF-kappaB may have both anti- and pro-apoptotic roles. TNFalpha stimulation, preceding DNA damaging irradiation, makes cells more resistant to irradiation-induced apoptosis, whereas the same TNFalpha stimulation, when preceded by irradiation, increases the apoptotic cell fraction. The finding suggests that diverse roles of NF-kappaB in apoptosis and cancer could be related to the dynamical context of activation of p53 and NF-kappaB pathways.