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Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis
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نویسنده
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jurado s. ,smyth i. ,van denderen b. ,tenis n. ,hammet a. ,hewitt k. ,ng j.-l. ,mcnees c.j. ,kozlov s.v. ,oka h. ,kobayashi m. ,conlan l.a. ,cole t.j. ,yamamoto k.-i. ,taniguchi y. ,takeda s. ,lavin m.f. ,heierhorst j.
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منبع
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plos genetics - 2010 - دوره : 6 - شماره : 10 - صفحه:1 -13
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چکیده
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Zn2+-finger proteins comprise one of the largest protein superfamilies with diverse biological functions. the atm substrate chk2-interacting zn2+-finger protein (asciz; also known as atmin and znf822) was originally linked to functions in the dna base damage response and has also been proposed to be an essential cofactor of the atm kinase. here we show that absence of asciz leads to p53-independent late-embryonic lethality in mice. asciz-deficient primary fibroblasts exhibit increased sensitivity to dna base damaging agents mms and h2o2,but asciz deletion or knock-down does not affect atm levels and activation in mouse,chicken,or human cells. unexpectedly,asciz-deficient embryos also exhibit severe respiratory tract defects with complete pulmonary agenesis and severe tracheal atresia. nkx2.1-expressing respiratory precursors are still specified in the absence of asciz,but fail to segregate properly within the ventral foregut,and as a consequence lung buds never form and separation of the trachea from the oesophagus stalls early. comparison of phenotypes suggests that asciz functions between wnt2-2b/ß-catenin and fgf10/fgf-receptor 2b signaling pathways in the mesodermal/endodermal crosstalk regulating early respiratory development. we also find that asciz can activate expression of reporter genes via its sq/tq-cluster domain in vitro,suggesting that it may exert its developmental functions as a transcription factor. altogether,the data indicate that,in addition to its role in the dna base damage response,asciz has separate developmental functions as an essential regulator of respiratory organogenesis. © 2010 jurado et al.
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آدرس
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st. vincent's institute of medical research,fitzroy,australia,department of medicine,st. vincent's hospital,the university of melbourne,fitzroy, Australia, department of biochemistry and molecular biology,department of anatomy and developmental biology,monash university,clayton, Australia, st. vincent's institute of medical research,fitzroy,australia,department of medicine,st. vincent's hospital,the university of melbourne,fitzroy, Australia, st. vincent's institute of medical research,fitzroy, Australia, st. vincent's institute of medical research,fitzroy,australia,csl ltd,parkville, Australia, st. vincent's institute of medical research,fitzroy, Australia, st. vincent's institute of medical research,fitzroy, Australia, st. vincent's institute of medical research,fitzroy,australia,childrens medical research institute,westmead, Australia, queensland institute of medical research,herston, Australia, department of radiation genetics,graduate school of medicine,kyoto university,kyoto,japan,terumo corporation,kanagawa, Japan, cancer research institute,kanazawa university,ishikawa, Japan, st. vincent's institute of medical research,fitzroy, Australia, department of biochemistry and molecular biology,department of anatomy and developmental biology,monash university,clayton, Australia, cancer research institute,kanazawa university,ishikawa, Japan, department of radiation genetics,graduate school of medicine,kyoto university,kyoto,japan,keio university school of medicine,tokyo, Japan, department of radiation genetics,graduate school of medicine,kyoto university,kyoto, Japan, queensland institute of medical research,herston,australia,central clinical division,university of queensland,royal brisbane hospital,herston, Australia, st. vincent's institute of medical research,fitzroy,australia,department of medicine,st. vincent's hospital,the university of melbourne,fitzroy, Australia
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Authors
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