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This Article OPEN ACCESS ARTICLE Full Text Full Text (PDF) Supplemental Research Data All Versions of this Article: gad.1648608v1 22/7/884    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Schlisio, S. Articles by Kaelin, W. G. PubMed PubMed Citation Articles by Schlisio, S. Articles by Kaelin, W. G., Jr. Social Bookmarking                   What's this?

The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; ² Department of Biochemistry and Center for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA; ³ Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 BE Amsterdam, The Netherlands; ⁴ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; ⁵ Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; ⁶ The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02141, USA; ⁷ Department of Medicine and Cellular and Structural Biology, San Antonio Cancer Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA; ⁸ Laboratoire de Biochimie and Hormonologie, Centre de Biologie et Pathologie, CHRU de Lille 59037, Lille cedex, France; ⁹ Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; ¹⁰ Division of Oncology, Children’s Hospital of Philadelphia, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ¹¹ Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bβ acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bβ maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bβ missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bβ is a pathogenic target of these deletions.

[Keywords: Apoptosis; kinesin; neuroblastoma; pheochromocytoma; prolyl hydroxylase]]

Received January 7, 2008; revised version accepted February 14, 2008.

E-MAIL william_kaelin{at}dfci.harvard.edu; FAX (617) 632-4760

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1648608.

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