From integrated signaling networks to high content microscopy:Systems approaches for TT21C
作者单位：Division of ToxicologyLeiden Academic Centre for Drug ResearchLeiden University
会议名称：《中国毒理学会第六届全国毒理学大会》
会议日期：2013年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
摘 要：Toxicogenomics has played a major role in the past decade to uncover cellular stress responses that underlie chemical-induced adverse reactions at the cellular as well as organ level and subsequently apply transcriptomics-based classifiers to predict adverse *** question remains what functional role these stress response pathways as well as the individual genes that underlie these stress responses play in the onset of *** have integrated transcrip-tomics, phosphoproteomics,and RNA interference (RNAi) approaches and used time-resolved live cell high content imaging of cellular stress responses to identify critical cell signaling components that determine the breaking point from adaptation to cell stress versus maladaptation and onset of cell *** pluripotent stem cells,DNA damage triggers loss-of-pluripotency and apopto-sis as a safeguard to exclude damaged DNA from the *** intricate DNA damage response (DDR) signaling network ensures that the response is proportional to the severity of the damage. We combined an RNAi screen targeting all kinases,phosphatases,and transcription factors with global transcriptomics and phosphopro-teomics to map the DDR in mouse embryonic stem cells treated with the DNA crosslinker cisplatin. Integrated networks derived from canonical pathways shared in all three datasets,were implicated in DNA damage repair,cell cycle and survival, and *** probing of these networks identified,amongst others a novel,p53-independent mode of DNA damage-induced Wnt signaling that limits *** findings reveal a balance between p53-mediated elimination of stem cells,through loss-of-pluripo-tency and apoptosis,and Wnt signaling that attenuates this response to tune the outcome of the *** currently explore several other newly identified signaling networks that modulate the outcome of the *** further reveal the complexity of dynamic toxicity-related signaling events we have developed systems micr