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Título: | FM19G11: A new modulator of hif that links mTOR activation with the DNA damage checkpoint pathways |
Autor: | Rodríguez-Jiménez, Francisco Javier; Moreno Manzano, Victoria; Mateos-Gregorio, Pablo; Royo, Inmaculada CSIC; Erceg, Slaven; Murguía, José Ramón CSIC ORCID; Sánchez-Puelles, José María CSIC ORCID | Fecha de publicación: | 2010 | Editor: | Landes Bioscience | Citación: | Cell Cycle 9(14):2875-2885(2010) | Resumen: | The network consisting of mTO R and p53 pathways is crucial to understanding a wide variety of physiological and pathological events, including cancer and aging. In addition, the HIF1α protein, a downstream target of mTO R, is a hallmark of different tumor types and was the desired strategy of many drug discovery efforts. Here we present the novel chemical entity FM19G11, a new modulator of HIF1α expression, which was used as a molecular tool to dissect and further characterize the cross-talk between these signaling cascades in human colon carcinoma cell lines. To our knowledge, FM19G11 is the first drug that triggers a DNA damage response (DDR) associated with G 1/S-phase arrest in a p53-dependent manner, due to rapid hyper-activation of the growth signaling pathway through mTO R. Assessment of colonies demonstrated that FM19G11 decreases the clonogenicity of HT29, HCT116/p53+/+ and HCT116/p53-/- cells. Moreover, FM19G11 causes significant lower colony growth in soft agar of p53-proficient human colon cancer cells. Consequently, p53 sensitizes human colon cancer cells to FM19G11 by significant reduction of their viability, lessening their colony formation capability and shrinking their anchorage-independent growth. Cell signaling studies served to assign a new mode of action to FM19G11, whose tumor-suppressant activity compromises the survival of functional p53 malignant cells. © 2010 Landes Bioscience. | URI: | http://hdl.handle.net/10261/72152 | DOI: | 10.4161/cc.9.14.12250 | Identificadores: | doi: 10.4161/cc.9.14.12250 issn: 1538-4101 e-issn: 1551-4005 |
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