Danovi, D; Cremona, CA; Machado-da-Silva, G; Basu, S; Noon, LA; Parrinello, S; Lloyd, AC; (2010) A Genetic Screen for Anchorage-Independent Proliferation in Mammalian Cells Identifies a Membrane-Bound Neuregulin. PLOS ONE , 5 (7) , Article e11774. 10.1371/journal.pone.0011774.
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Anchorage-independent proliferation is a hallmark of oncogenic transformation and is thought to be conducive to proliferation of cancer cells away from their site of origin. We have previously reported that primary Schwann cells expressing the SV40 Large T antigen (LT) are not fully transformed in that they maintain a strict requirement for attachment, requiring a further genetic change, such as oncogenic Ras, to gain anchorage-independence. Using the LT-expressing cells, we performed a genetic screen for anchorage-independent proliferation and identified Sensory and Motor Neuron Derived Factor (SMDF), a transmembrane class III isoform of Neuregulin 1. In contrast to oncogenic Ras, SMDF induced enhanced proliferation in normal primary Schwann cells but did not trigger cellular senescence. In cooperation with LT, SMDF drove anchorage-independent proliferation, loss of contact inhibition and tumourigenicity. This transforming ability was shared with membrane-bound class III but not secreted class I isoforms of Neuregulin, indicating a distinct mechanism of action. Importantly, we show that despite being membrane-bound signalling molecules, class III neuregulins transform via a cell intrinsic mechanism, as a result of constitutive, elevated levels of ErbB signalling at high cell density and in anchorage-free conditions. This novel transforming mechanism may provide new targets for cancer therapy.
|Title:||A Genetic Screen for Anchorage-Independent Proliferation in Mammalian Cells Identifies a Membrane-Bound Neuregulin|
|Open access status:||An open access publication. A version is also available from UCL Discovery.|
|Additional information:||© 2010 Danovi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was funded by a Cancer Research UK Programme Grant. Davide Danovi was supported by an European Molecular Biology Organization fellowship. Simona Parrinello was supported by a Dorothy Hodgkin Fellowship. Catherine Cremona was supported by a Medical Research Council PHD programme. Gisela Machado da Silva was supported by a studentship from Fundacao para a Ciencia e a Tecnologia. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.|
|Keywords:||NERVE SHEATH TUMORS, SCHWANN-CELL, SIGNALING PATHWAY, GROWTH-FACTORS, SENESCENCE, CANCER, DIFFERENTIATION, TRANSFORMATION, TUMORIGENESIS, ACCUMULATION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Wolfson Institute and Cancer Institute Administration > Cancer Institute > Research Department of Cancer Biology|
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