Location: the Auditorium in the new Research Building at 13.00-14.30 hrs.

Programme:

Kjersti Flatmark, MD, PhD – Department of Tumor Biology and Surgical Oncology, The Norwegian Radium Hospital
Title to be announced soon

Dr Ian Mills – Prostate Cancer Research Group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo
Title to be announced soon

The seminar is open to the Institute for Cancer Research and the Division of Surgery & Cancer Medicine

Welcome to all of you!

Autophagy, a cellular process that involves lysosomal degradation of portions of cytoplasm, plays a role in tumour suppression by degrading potentially harmful damaged organelles. This process has also been implicated in programmed cell death, but the molecular mechanisms have remained elusive so far. Now, Nezis and co-workers have identified a novel link between autophagy and activation of caspases, proteases that are key effectors of programmed cell death. Using oogenesis in the fruit fly Drosophila melanogaster as model system, Nezis and colleagues have found that so-called nurse cells, which provide nutrients to the forming oocyte, die at a well-defined stage of late oogenesis, and that this requires autophagy. In the present paper, Nezis and co-workers show that programmed cell death of nurse cells requires degradation of a caspase inhibitor, dBruce. Importantly, degradation of dBruce through autophagy turns out to trigger caspase activation and cell death. This is the first description of a mechanistic connection between autophagy and caspase-dependent cell death, and these findings are likely to have implications for other programmed cell death processes as well. Parts of these studies were in collaboration with Prof. Eric Baehrecke at the University of Massachusetts, one of the leaders in the field of programmed cell death, and with the group of Terje Johansen at the University of Tromsø, who are internationally reknowned for their studies of autophagy.

Figure legend (click figure to enlarge):
The caspase inhibitor dBruce (red) localizes to autophagosomes (green) in nurse cells during late oogenesis in Drosophila. Nuclei are stained in blue.

Link to the article:
Nezis IP, Shravage BV, Sagona AP, Lamark T, Bjørkøy G, Johansen T, Rusten TE, Brech A, Baehrecke EH, Stenmark H.
Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis
J Cell Biol. 2010 Aug 23;190(4):523-31. Epub 2010 Aug 16.

Programme:

14.00-14.30: Trond Stokke – Dept. of Radiation Biology, Institute for Cancer Research:
Presentation of the Flow Cytometry Core Facility

14.30-14.45: Coffee break

14.45-15.15: June Helen Myklebust – CCB and Dept. of Immunology, Institute for Cancer Research:
Possibilities with multiparameter flow cytometry

The Scientific Council consists of highly qualified scientists, selected on the basis of their technical competence in cancer research and allied fields. Members of the Scientific Council are appointed as experts and not as representatives of Participating States. The purpose of this Council is, among other things, to make periodical evaluations of IARC’s activities, to make recommendations on the programme of permanent activities and to prepare special projects to be submitted to the Governing Council.

To read an interview (in Norwegian only) with Edgar Rivedal published on the homepage of The Research Council of Norway, please click here: Ruster seg mot drastisk kreftøkning.

Integrins are heterodimeric membrane proteins that form contacts between cytosolic cytoskeletal components and the extracellular matrix. Because of their involvement in cell migration, which is crucial for tumour invasion, Lobert and co-workers have been studied the regulation of integrin molecules in migrating cells. It is well known that endocytosis and subsequent recycling of the fibronectin receptor, alpha5beta1 integrin, is crucial for cell migration through controlling the correct formation of adhesion site at the leading lamellopodium of migrating cells. Through microscopic studies of migrating fibroblasts, Lobert and colleagues made the unanticipated observation that a substantial fraction of integrin molecules were found in multivesicular endosomes and late endosomes, organelles normally associated with degradative functions. The authors went on to show that a fraction of alpha5beta1 integrin is indeed degraded in lysosomes, and that the sorting to these organelles is mediated by fibronectin-induced ubiquitination of the alpha5 chain, followed by recognition and sorting of the ubiquitinated integrins by the endosomal sorting complex required for transport (ESCRT) machinery in endosomal membranes. Importantly, interference with this sorting inhibits cell migration, revealing that lysosomal sorting of alpha5beta1 integrin is crucial for proper cell migration. Lobert and colleagues conclude that it is important for the migrating cell to degrade fibronectin-bound integrin molecules that are internalised, since recycling of such molecules would otherwise cause dysfunctional adhesion sites (see Figure – click to enlarge).

Lobert comments that “we were surprised to make these observations, since everyone in the integrin field has been assuming that essentially all endocytosed integrin molecules are recycled. The importance of lysosomal trafficking of integrins in fibroblast migration raises the interesting question whether such trafficking could also be important in tumour cell migration, and whether this may be targeted in cancer therapy.”

Figure text:
Endocytosis and recycling of alpha5 (red) and beta1 (purple) integrin heterodimers at the leading edge of a migrating cell is important for the correct turnover and assembly of adhesion sites. The present paper shows that those integrin molecules that are internalised in complex with fibronectin (green) are ubiquitinated and thereafter sorted by the ESCRT machinery to lysosomes via multivesicular endosomes (MVEs). This prevents recycling of ligand-bound integrins that would otherwise form nonproductive adhesion sites.

Link to the article at www.cell.com
Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes.
Lobert VH, Brech A, Pedersen NM, Wesche J, Oppelt A, Malerød L, Stenmark H.
Dev Cell. 2010 Jul 20;19(1):148-59.

Update:
In the August 2010 update of Nature Cell Migration Gateway you can read the following comment on Viola Lobert’s featured article:
ESCRTed by integrin degradation

PMID: 20587517

PMID: 20505157

PMID: 20510257

PMID: 20551902