Anti-Apoptotic NF-κB and “Gain of Function” mutp53 in Concert Act Pro-Apoptotic in Response to UVB+IL-1 via Enhanced TNF Production

Abstract

In response to genotoxic stress, including UVB radiation, transcription factors NF-κB and p53 inevitably influence the cellular fate. Loss of p53 function has been attributed to malignant transformation and interferes with therapeutic interventions, whereas “gain of function” mutants even enhance tumor promotion. Constitutive NF-κB activation is linked to tumor maintenance and resistance against chemotherapy. The cross talk between p53 and NF-κB, however, is still under debate. Using the non-transformed keratinocyte cell line HaCaT, we shed light on the interplay between p53 and NF-κB by providing clear evidence that chronically activated NF-κB together with designated “gain of function” mutp53 promotes apoptosis via cooperative tumor necrosis factor (TNF) production in response to UVB+IL-1. Performing chromatin immunoprecipitation analysis we demonstrate that both transcription factors bind to the TNF promoter, whereas UVB-induced inhibition of Ser-Thr-phosphatase protein phosphatase 2A facilitates prolonged phosphorylation of NF-κB and the transcriptional cofactor cAMP response element–binding protein, both being required for extended TNF transcription. Thus, two major anti-apoptotic factors, NF-κB and mutp53, in concert may generate pro-apoptotic responses. As human skin is constantly exposed to UVB, causing IL-1 production as well, we hypothesize that the remarkable amount of hotspot p53 mutations within the epidermis (4%) may serve a protective function to eliminate precancerous cells at an early stage.