Identification of PP2A as a crucial regulator of the NF-kappaB feedback loop: its inhibition by UVB turns NF-kappaB into a pro-apoptotic factor.

Although nuclear factor-kappaB (NF-kappaB) usually exerts anti-apoptotic activity, upon activation by interleukin-1 (IL-1) it enhances ultraviolet-B radiation (UVB)-induced apoptosis. This paradoxical effect is associated with NF-kappaB-dependent pronounced secretion of tumour necrosis factor-alpha (TNF) which activates TNF-R1 in an autocrine fashion to enhance UVB-induced apoptosis. We demonstrate that sustained TNF transcription in UVB+IL-1-treated cells involves complete abrogation of the negative feedback loop of NF-kappaB preventing IkappaBalpha resynthesis, hence allowing uncontrolled NF-kappaB activity. We show that IkappaBalpha is not transcriptionally inhibited but resynthesized protein is immediately marked for degradation due to persistent inhibitor of kappaB kinasebeta (IKKbeta) activity. Continuous IKKbeta phosphorylation and activation is caused by UVB-mediated inhibition of the phosphatase PP2A. This study demonstrates that the cellular response to different NF-kappaB activators may be converted to the opposite reaction when both stimuli act in concert. Our data shed new light on the significance of negative feedback regulation of NF-kappaB and identifies PP2A as the key regulator of this process.