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Id2 suppression of p15 counters TGF‐β‐mediated growth inhibition of melanoma cells
Authors:Natalie C Schlegel  Ossia M Eichhoff  Silvio Hemmi  Sabine Werner  Reinhard Dummer  Keith S Hoek
Institution:1. Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland;2. These authors contributed equally.;3. Faculty of Mathematics and Natural Sciences, Institute of Molecular Biology, University of Zürich, Zürich, Switzerland;4. Department of Biology, Institute of Cell Biology,ETH Zurich, Zurich, Switzerland
Abstract:Proliferative resistance to transforming growth factor β (TGF‐β) is regarded as a critical turning point in the malignant progression of many cancer types. In melanoma this resistance is associated with more aggressive metastatic behaviour. A recent study by our group identified proliferative and invasive subtypes of melanoma cultures and found that these are, respectively, susceptible and resistant to TGF‐β suppression of proliferation. Here, using previously characterised proliferative and invasive phenotype melanoma cultures, we explored molecular responses involved in modulating susceptibility to TGF‐β‐mediated inhibition of proliferation. The Id2 gene was identified as being expressed more strongly in invasive phenotype cells less susceptible to TGF‐β repression than in proliferative phenotype cells. We correlated TGF‐β repression of Id2 gene expression in proliferative phenotype cells with p15Ink4b induction and cell cycle arrest. Furthermore, ectopic Id2 expression in proliferative phenotype cells counteracted p15Ink4b induction and consequently protected them from TGF‐β‐mediated inhibition of proliferation. We conclude that transition to increased aggressiveness in melanoma cells requires Id2 upregulation to suppress TGF‐β induction of p15Ink4b and thus help to circumvent TGF‐β‐mediated inhibition of proliferation.
Keywords:Id2  p15  cytokine susceptibility
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