Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins

Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFβ-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFβ. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-κB family member RELB. We show that RELB represses TGFβ target promoters independently of DNA binding at NF-κB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFβ gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth

The epigenetic landscape of renal cancer

This is an accepted manuscript of an article published by Nature in Nature Reviews: Nephrology on 28/11/2016, available online: https://doi.org/10.1038/nrneph.2016.168 The accepted version of the publication may differ from the final published version.The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling. In this Review, we discuss how altered DNA methylation, microRNA dysregulation and mutations in histone-modifying enzymes disrupt cellular pathways in renal cancers

Volume and market share of anti-epileptic drugs in The Netherlands: impact of new drugs.

Item does not contain fulltextOBJECTIVE: In the past decade, several new anti-epileptic drugs (AEDs) were introduced in The Netherlands. These new drugs, one of which is lamotrigine, are 6 to 10 times more expensive than conventional anti-convulsants. In 1997, the high cost of lamotrigine, together with a lack of clinical data supporting its superiority over conventional drugs, prompted the Dutch Health Insurance Board to release a guideline in which the use of lamotrigine was restricted to difficult-to-treat patients. Other new drugs that were marketed after 1997 also became subject to this guideline. The utilisation of new AEDs and the cost consequences are the subject of this paper. METHODS: Data from extramurally prescribed AEDs was obtained from the Dutch Drug Information Project, which is a database containing prescriptions for about 5.5 million inhabitants of the Netherlands. This data was used to study the impact of new AEDs on volume and market share of AEDs in the period from 1995 to 2001 in The Netherlands. RESULTS: Between 1995 and 2001, the total volume of AEDs increased by 130%, 60% of which consisted of new AEDs. Gabapentin, lamotrigine and oxcarbazepine were the most frequently prescribed new compounds. The volume share of new AEDs increased from 5% in 1995 to 18% in 2001. The market share amounted to 21.5 million euros in 1995 and rose to 47 million euros in 2001; 80% of this increase was due to the introduction of new AEDs. DISCUSSION: Although in 2001 the volume share of new AEDs was still modest, their introduction has led to a strong increase in the cost. New data is emerging on the effectiveness and cost-benefit sum of the new AEDs; this may change the place in therapy of these drugs. Because of their strong potential to force up cost, the positioning of new AEDs requires further attention