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Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ.
Sci Rep. 2019 07 25; 9(1):10811.SR

Abstract

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.

Authors+Show Affiliations

Stanford Cardiovascular Institute and the Department of Medicine, Stanford University, Stanford, CA, 94305, USA. Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.Icagen, Oro Valley, AZ, 85755, USA.Icagen, Oro Valley, AZ, 85755, USA.Stanford Cardiovascular Institute and the Department of Medicine, Stanford University, Stanford, CA, 94305, USA.Stanford Cardiovascular Institute and the Department of Medicine, Stanford University, Stanford, CA, 94305, USA.Human BioMolecular Research Institute, San Diego, CA, 92121, USA.University Medical Center Ulm, 89081, Ulm, Germany.Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.Human BioMolecular Research Institute, San Diego, CA, 92121, USA.Regencor, Los Altos, CA, 94022, USA.Sanofi, 91380, Chilly-Mazarin, France.Icagen, Oro Valley, AZ, 85755, USA. Belltree Consulting, L.L.C., Tucson, AZ, 85745, USA.Stanford Cardiovascular Institute and the Department of Medicine, Stanford University, Stanford, CA, 94305, USA. mmercola@stanford.edu. Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. mmercola@stanford.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31346210

Citation

Hurtado, Cecilia, et al. "Disruption of NOTCH Signaling By a Small Molecule Inhibitor of the Transcription Factor RBPJ." Scientific Reports, vol. 9, no. 1, 2019, p. 10811.
Hurtado C, Safarova A, Smith M, et al. Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ. Sci Rep. 2019;9(1):10811.
Hurtado, C., Safarova, A., Smith, M., Chung, R., Bruyneel, A. A. N., Gomez-Galeno, J., Oswald, F., Larson, C. J., Cashman, J. R., Ruiz-Lozano, P., Janiak, P., Suzuki, T., & Mercola, M. (2019). Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ. Scientific Reports, 9(1), 10811. https://doi.org/10.1038/s41598-019-46948-5
Hurtado C, et al. Disruption of NOTCH Signaling By a Small Molecule Inhibitor of the Transcription Factor RBPJ. Sci Rep. 2019 07 25;9(1):10811. PubMed PMID: 31346210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ. AU - Hurtado,Cecilia, AU - Safarova,Alena, AU - Smith,Michael, AU - Chung,Raeeun, AU - Bruyneel,Arne A N, AU - Gomez-Galeno,Jorge, AU - Oswald,Franz, AU - Larson,Christopher J, AU - Cashman,John R, AU - Ruiz-Lozano,Pilar, AU - Janiak,Philip, AU - Suzuki,Teri, AU - Mercola,Mark, Y1 - 2019/07/25/ PY - 2018/10/22/received PY - 2019/07/03/accepted PY - 2019/7/27/entrez PY - 2019/7/28/pubmed PY - 2019/7/28/medline SP - 10811 EP - 10811 JF - Scientific reports JO - Sci Rep VL - 9 IS - 1 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/31346210/Disruption_of_NOTCH_signaling_by_a_small_molecule_inhibitor_of_the_transcription_factor_RBPJ_ L2 - http://dx.doi.org/10.1038/s41598-019-46948-5 DB - PRIME DP - Unbound Medicine ER -
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