Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ
| Autor: | Jorge Gomez-Galeno, Pilar Ruiz-Lozano, Philip Janiak, Raeeun Chung, Christopher J. Larson, Alena Safarova, Suzuki Teri, Cecilia Hurtado, John R. Cashman, Franz Oswald, Arne A. N. Bruyneel, Mark Mercola, Michael L. Smith |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Scaffold protein GAMMA-SECRETASE Notch signaling pathway lcsh:Medicine Article Cell Line Myoblasts PATHWAY 03 medical and health sciences 0302 clinical medicine Transcriptional repressor complex SUPPRESSOR Gene expression Humans lcsh:Science Transcription factor Multidisciplinary Science & Technology Receptors Notch RBPJ Chemistry Effector Drug discovery lcsh:R Cell Differentiation Cell biology Multidisciplinary Sciences 030104 developmental biology DIFFERENTIATION TARGET Gene Expression Regulation Immunoglobulin J Recombination Signal Sequence-Binding Protein CELLS Screening Science & Technology - Other Topics lcsh:Q C2C12 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-9 (2019) Scientific Reports |
| Popis: | NOTCH plays a pivotal role during normal development and in congenital disorders and cancer. γ-secretase inhibitors are commonly used to probe NOTCH function, but also block processing of numerous other proteins. We discovered a new class of small molecule inhibitor that disrupts the interaction between NOTCH and RBPJ, which is the main transcriptional effector of NOTCH signaling. RBPJ Inhibitor-1 (RIN1) also blocked the functional interaction of RBPJ with SHARP, a scaffold protein that forms a transcriptional repressor complex with RBPJ in the absence of NOTCH signaling. RIN1 induced changes in gene expression that resembled siRNA silencing of RBPJ rather than inhibition at the level of NOTCH itself. Consistent with disruption of NOTCH signaling, RIN1 inhibited the proliferation of hematologic cancer cell lines and promoted skeletal muscle differentiation from C2C12 myoblasts. Thus, RIN1 inhibits RBPJ in its repressing and activating contexts, and can be exploited for chemical biology and therapeutic applications. |
| Databáze: | OpenAIRE |
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