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Modulating the Strength and Threshold of NOTCH Oncogenic Signals by mir-181a-1/b-1
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نویسنده
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fragoso r. ,mao t. ,wang s. ,schaffert s. ,gong x. ,yue s. ,luong r. ,min h. ,yashiro-ohtani y. ,davis m. ,pear w. ,chen c.-z.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 8
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چکیده
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Oncogenes,which are essential for tumor initiation,development,and maintenance,are valuable targets for cancer therapy. however,it remains a challenge to effectively inhibit oncogene activity by targeting their downstream pathways without causing significant toxicity to normal tissues. here we show that deletion of mir-181a-1/b-1 expression inhibits the development of notch1 oncogene-induced t cell acute lymphoblastic leukemia (t-all). mir-181a-1/b-1 controls the strength and threshold of notch activity in tumorigenesis in part by dampening multiple negative feedback regulators downstream of notch and pre-t cell receptor (tcr) signaling pathways. importantly,although notch oncogenes utilize normal thymic progenitor cell genetic programs for tumor transformation,comparative analyses of mir-181a-1/b-1 function in normal thymocyte and tumor development demonstrate that mir-181a-1/b-1 can be specifically targeted to inhibit tumor development with little toxicity to normal development. finally,we demonstrate that mir-181a-1/b-1,but not mir-181a-2b-2 and mir-181-c/d,controls the development of normal thymic t cells and leukemia cells. together,these results illustrate that notch oncogene activity in tumor development can be selectively inhibited by targeting the molecular networks controlled by mir-181a-1/b-1. © 2012 fragoso et al.
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آدرس
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department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca, United States, department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca, United States, department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca, United States, department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca, United States, department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca, United States, department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca, United States, department of comparative medicine,stanford university school of medicine,stanford,ca, United States, department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca,united states,chung-ang university college of pharmacy,seoul, South Korea, abramson family cancer research institute,university of pennsylvania school of medicine,philadelphia,pa,united states,department of pathology and laboratory medicine,university of pennsylvania school of medicine,philadelphia,pa, United States, howard hughes medical institute and department of microbiology and immunology,stanford university school of medicine,stanford,ca, United States, abramson family cancer research institute,university of pennsylvania school of medicine,philadelphia,pa,united states,department of pathology and laboratory medicine,university of pennsylvania school of medicine,philadelphia,pa, United States, department of microbiology and immunology,stanford university school of medicine,stanford,ca,united states,baxter laboratory for stem cell biology,stanford university school of medicine,stanford,ca, United States
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Authors
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