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Wong, Samantha; Tan, Yu Xuan; Loh, Abigail Yi Ting; Tan, Kiat Yi; Lee, Hane; Aziz, Zainab; Nelson, Stanley F.; Ozkan, Engin; Kayserili, Hülya; Escande-Beillard, Nathalie; Reversade, Bruno
<?xml version='1.0' encoding='UTF-8'?> <record xmlns="http://www.loc.gov/MARC21/slim"> <leader>00000nam##2200000uu#4500</leader> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Tan, Yu Xuan</subfield> <subfield code="u">ASTAR, Inst Mol & Cellular Biol, Singapore, Singapore</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Loh, Abigail Yi Ting</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Tan, Kiat Yi</subfield> <subfield code="u">ASTAR, Inst Mol & Cellular Biol, Singapore, Singapore</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Lee, Hane</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Aziz, Zainab</subfield> <subfield code="u">Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL USA</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Nelson, Stanley F.</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Ozkan, Engin</subfield> <subfield code="u">Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL USA</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Kayserili, Hülya</subfield> <subfield code="u">Koc Univ, Sch Med, Dept Med Genet, Istanbul, Turkiye</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Escande-Beillard, Nathalie</subfield> </datafield> <datafield tag="700" ind1=" " ind2=" "> <subfield code="a">Reversade, Bruno</subfield> </datafield> <datafield tag="909" ind1="C" ind2="4"> <subfield code="p">EMBO MOLECULAR MEDICINE</subfield> <subfield code="v">15</subfield> <subfield code="n">5</subfield> <subfield code="c">15</subfield> </datafield> <datafield tag="980" ind1=" " ind2=" "> <subfield code="a">user-tubitak-destekli-proje-yayinlari</subfield> </datafield> <datafield tag="540" ind1=" " ind2=" "> <subfield code="a">Creative Commons Attribution</subfield> <subfield code="u">http://www.opendefinition.org/licenses/cc-by</subfield> </datafield> <datafield tag="024" ind1=" " ind2=" "> <subfield code="a">10.15252/emmm.202217078</subfield> <subfield code="2">doi</subfield> </datafield> <datafield tag="245" ind1=" " ind2=" "> <subfield code="a">RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis</subfield> </datafield> <datafield tag="100" ind1=" " ind2=" "> <subfield code="a">Wong, Samantha</subfield> </datafield> <datafield tag="909" ind1="C" ind2="O"> <subfield code="o">oai:aperta.ulakbim.gov.tr:270832</subfield> <subfield code="p">user-tubitak-destekli-proje-yayinlari</subfield> </datafield> <datafield tag="650" ind1="1" ind2="7"> <subfield code="2">opendefinition.org</subfield> <subfield code="a">cc-by</subfield> </datafield> <datafield tag="260" ind1=" " ind2=" "> <subfield code="c">2023-01-01</subfield> </datafield> <datafield tag="856" ind1="4" ind2=" "> <subfield code="u">https://aperta.ulakbim.gov.trrecord/270832/files/bib-42cd92d6-83ed-4880-90ae-644180a121d9.txt</subfield> <subfield code="z">md5:ba7c1fe640623cd6dc7b440c1ed4dee7</subfield> <subfield code="s">276</subfield> </datafield> <datafield tag="542" ind1=" " ind2=" "> <subfield code="l">open</subfield> </datafield> <controlfield tag="005">20240607161709.0</controlfield> <controlfield tag="001">270832</controlfield> <datafield tag="980" ind1=" " ind2=" "> <subfield code="a">publication</subfield> <subfield code="b">article</subfield> </datafield> <datafield tag="520" ind1=" " ind2=" "> <subfield code="a"><p>Somatic and germline gain-of-function point mutations in RAF, one of the first oncogenes to be discovered in humans, delineate a group of tumor-prone syndromes known as the RASopathies. In this study, we document the first human phenotype resulting from the germline loss-of-function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met variant segregating with a neonatal lethal syndrome with cutaneous, craniofacial, cardiac, and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: (i) ensure RAF1's stability and phosphorylation, (ii) maintain its kinase activity toward substrates of the MAPK pathway, and (iii) protect from stress-induced apoptosis mediated by ASK1. In Xenopus embryos, mutant RAF1(T543M) failed to phenocopy the effects of normal and overactive FGF/MAPK signaling, confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel lethal syndrome with progeroid features, highlighting the importance of RTK signaling for human development and homeostasis.</p></subfield> </datafield> </record>
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