| 1. |
- Bertolotto, Corine, et al.
(författare)
-
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
- 2011
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 480:7375, s. 94-98
-
Tidskriftsartikel (refereegranskat)abstract
- So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
|
|
| 2. |
- Palsson, Gisli, et al.
(författare)
-
Reconceptualizing the 'Anthropos' in the Anthropocene : Integrating the social sciences and humanities in global environmental change research
- 2013
-
Ingår i: Environmental Science and Policy. - : Elsevier BV. - 1462-9011 .- 1873-6416. ; 28, s. 3-13
-
Tidskriftsartikel (refereegranskat)abstract
- There is growing recognition that humans are faced with a critical and narrowing window of opportunity to halt or reverse some of the key indicators involved in the environmental crisis. Given human activities' scale and impact, as well as the overly narrow perspectives of environmental research's dominant natural sciences, a major effort is necessary to place the perspectives and insights of the humanities' and social sciences' perspectives and insights at the forefront. Such effort will require developing integrated approaches, projects, and institutions that truly do so. This article's goal is to help mobilize the social sciences and the humanities on the topic of sustainability transitions, but also call for a meaningful research agenda to acknowledge the profound implications of the advent of the Anthropocene epoch. We formulate the need for an innovative research agenda based on a careful consideration of the changing human condition as linked to global environmental change. The humanities and social sciences will need to change and adapt to this pressing, historic task.
|
|
