notch signaling activation suppresses v-src-induced transformation of neural cells by restoring tgf-β-mediated differentiationnotch信号激活抑制v-src-induced变换恢复tgf-β-mediated分化的神经细胞.pdfVIP

Notch Signaling Activation Suppresses v-Src-Induced Transformation of Neural Cells by Restoring TGF-b- Mediated Differentiation Samira Amarir, Maria Marx, Georges Calothy* CNRS UMR3347/INSERM U1021, Institut Curie-Section Recherche, Orsay, France Abstract Background: We have been investigating how interruption of differentiation contributes to the oncogenic process and the possibility to reverse the transformed phenotype by restoring differentiation. In a previous report, we correlated the capacity of intracellular Notch (ICN) to suppress v-Src-mediated transformation of quail neuroretina (QNR/v-srcts) cells with the acquisition by these undifferentiated cells of glial differentiation markers. Methodology/Principal Findings: In this work, we have identified autocrine TGF-b3 signaling activation as a major effector of Notch-induced phenotypic changes, sufficient to induce transition in differentiation markers expression, suppress morphological transformation and significantly inhibit anchorage-independent growth. We also show that this signaling is constitutive of and contributes to ex-vivo autonomous QNR cell differentiation and that its down-regulation is essential to achieve v-Src-induced transformation. Conclusions/Significance: These results support the possibility that Notch signaling induces differentiation and suppresses transformation by a novel mechanism, involving secreted proteins. They also underline the importance of extracellular signals in controlling the balance between normal and transformed phenotypes. Citation: Amarir S, Marx M, Calothy G (2010) Notch Signaling Activation Suppresses v-Src-Induced Transformation of Neural Cells by Restoring TGF-b-Mediated Differentiation. PLoS ONE 5(10): e13572. doi:10.1371/j