Document Detail


FM19G11: A new modulator of HIF that links mTOR activation with the DNA damage checkpoint pathways.
MedLine Citation:
PMID:  20676050     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The network consisting of mTOR and p53 pathways is crucial to understanding a wide variety of physiological and pathological events, including cancer and aging. In addition, the HIF1alpha protein, a downstream target of mTOR, 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 HIF1alpha 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 mTOR. 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.
Authors:
Francisco Javier Rodríguez-Jiménez; Victoria Moreno-Manzano; Pablo Mateos-Gregorio; Inmaculada Royo; Slaven Erceg; José Ramón Murguia; Jose María Sánchez-Puelles
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-03
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-08-16     Completed Date:  2011-02-03     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2803-13     Citation Subset:  IM    
Affiliation:
Cellular Reprogramming Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain. fjrodriguezjim@hotmail.com
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MeSH Terms
Descriptor/Qualifier:
Benzamides / chemistry,  pharmacology*
Benzoates / chemistry,  pharmacology*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
DNA Damage*
DNA-Binding Proteins / metabolism
G1 Phase
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / agonists,  antagonists & inhibitors,  metabolism*
Kinetics
Phosphorylation
Protein-Serine-Threonine Kinases / metabolism
S Phase
Signal Transduction*
TOR Serine-Threonine Kinases / metabolism*
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins / metabolism
Chemical
Reg. No./Substance:
0/Benzamides; 0/Benzoates; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/FM19G11; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; EC 2.7.1.-/ATR protein, human; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein

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