SUMMARY The slippery zone situated below the peristome inside pitchers of most carnivorous plants from the genus Nepenthes is covered with a thick layer of epicuticular wax. This slippery zone is reported to play a crucial role in animal trapping and prey retention. In N. alata, the wax coverage consists of two clearly distinguished layers. These layers differ in their structure, chemical composition and mechanical properties, and they reduce the insect attachment in different ways. The lower layer resembles foam, composed of interconnected membraneous platelets protruding from the surface at acute angles. The upper layer consists of densely placed separate irregular platelets, located perpendicular to the subjacent layer. Crystals of the upper layer bear small stalks, directed downwards and providing connections to the lower layer. These morphological distinctions correlate with differences in the chemical composition of waxes. The compound classes of alkanes, aldehydes, primary alcohols, free fatty acids, esters and triterpenoids occurred in extracts from both wax layers, but in different proportions. Chain length distributions in aliphatics were different in extracts from the lower and the upper wax layers. Waxes of the upper and lower layers exhibited different mechanical properties: wax of the lower layer is harder and stiffer than that of the upper layer. Moreover, crystals of the upper layer are brittle and may be easily exfoliated or broken to tiny pieces. Laboratory experiments using tethered insects showed that both wax layers reduce the attachment force of insects. It is assumed that a decrease in insect attachment on the two distinct wax layers is provided by the two different mechanisms: (1) crystals of the upper wax layer contaminate insects'adhesive pads; (2) the lower wax layer leads to a reduction of the real contact area of insects' feet with the plant surface.

Nuclear factor-jB (NF-jB) and p53 critically determine cancer development and progression. Defining the cross talk between these transcription factors can expand our knowledge on molecular mechanisms of tumorigenesis. Here, we show that induction of replicational stress activates NF-jB p65 and triggers its interaction with p53 in the nucleus. Experiments with knockout cells show that p65 and p53 are both required for enhanced NF-jB activity during S-phase checkpoint activation involving ataxiatelangiectasia mutated and checkpoint kinase-1. Accordingly, the pro-inflammatory cytokine tumor necrosis factora (TNF-a) also triggers formation of a transcriptionally active complex containing nuclear p65 and p53 on jB response elements. Gene expression analyses revealed that, independent of NF-jB activation in the cytosol, TNFinduced NF-jB-directed gene expression relies on p53. Hence, p53 is unexpectedly necessary for NF-jB-mediated gene expression induced by atypical and classical stimuli. Remarkably, data from gain-and loss-of function approaches argue that anti-apoptotic NF-jB p65 activity is constitutively evoked by a p53 hot-spot mutant frequently found in tumors. Our observations suggest explanations for the outstanding question why p53 mutations rather than p53 deletions arise in tumors of various origins.

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer death in the western world, with a 5-year survival rate below 5%. Murine double minute 2 (Mdm2) is an important negative regulator of the tumor suppressor p53. Reactivation of wild-type p53 is a promising treatment strategy, and inhibitors of Mdm2 have already entered clinical trials. To investigate the effects of Mdm2 inhibitors in PDAC, we used a murine cell line platform with a genetically defined status of p53. Here, we describe that Mdm2 inhibitors can act on a subset of murine PDAC cell lines p53 independently. Furthermore, we observed that Mdm2 inhibitors increase the sensitivity of murine PDAC cell lines toward topoisomerase II inhibitors by inducing effector caspase-independent cell death. The combination of Mdm2 inhibitors with topoisomerase II inhibitors acts independent of the survival factor NFjB/RelA. Mechanistically, Mdm2 inhibitors increase topoisomerase II inhibitor-induced DNA double-strand breaks. We show that Mdm2 binds to Nbs1 of the Mre11-Rad50-Nijmegen breakage syndrome (Nbs) 1 DNA repair complex. In addition, we provide evidence that Mdm2 inhibitors delay DNA repair. These findings may help to design novel therapeutic strategies to overcome therapeutic resistance of PDAC.Murine double minute 2 [Mdm2; termed as human double minute 2 (HDM2) in Homo sapiens] is a critical negative regulator of the transcription factor and tumor suppressor p53.

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