Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity.

Stem Cells
Xiuli JiangMark D Johnson

Abstract

Glioblastoma contains a hierarchy of stem-like cancer cells, but how this hierarchy is established is unclear. Here, we show that asymmetric Numb localization specifies glioblastoma stem-like cell (GSC) fate in a manner that does not require Notch inhibition. Numb is asymmetrically localized to CD133-hi GSCs. The predominant Numb isoform, Numb4, decreases Notch and promotes a CD133-hi, radial glial-like phenotype. However, upregulation of a novel Numb isoform, Numb4 delta 7 (Numb4d7), increases Notch and AKT activation while nevertheless maintaining CD133-hi fate specification. Numb knockdown increases Notch and promotes growth while favoring a CD133-lo, glial progenitor-like phenotype. We report the novel finding that Numb4 (but not Numb4d7) promotes SCF(Fbw7) ubiquitin ligase assembly and activation to increase Notch degradation. However, both Numb isoforms decrease epidermal growth factor receptor (EGFR) expression, thereby regulating GSC fate. Small molecule inhibition of EGFR activity phenocopies the effect of Numb on CD133 and Pax6. Clinically, homozygous NUMB deletions and low Numb mRNA expression occur primarily in a subgroup of proneural glioblastomas. Higher Numb expression is found in classical and mesenchymal gliobl...Continue Reading

References

Mar 1, 1992·Mechanisms of Development·L A Abbott, J E Natzle
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·J M VerdiH D Lipshitz
May 16, 2002·Proceedings of the National Academy of Sciences of the United States of America·Roberta RoncaratiLuciano D'Adamio
Apr 19, 2003·The Journal of Biological Chemistry·Melanie A McGill, C Jane McGlade
Oct 30, 2003·The Journal of Biological Chemistry·Hadassah SadeApurva Sarin
Mar 24, 2004·Genes & Development·Olga KlezovitchValeri Vasioukhin
Jan 7, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Chris EnglundRobert F Hevner
Feb 2, 2006·Molecular and Cellular Biology·Shih-Ching Lo, Mark Hannink
Jul 25, 2006·Proceedings of the National Academy of Sciences of the United States of America·Gil BornsteinAvram Hershko
Nov 23, 2006·Nature Cell Biology·Lucia Di MarcotullioAlberto Gulino
Jan 4, 2008·Nature·Ivan N ColalucaPier Paolo Di Fiore
May 1, 2008·Annual Review of Plant Biology·Sara K Hotton, Judy Callis
Sep 2, 2008·Molecular and Cellular Neurosciences·Niklas ThonRoland Goldbrunner
Sep 6, 2008·Nature·UNKNOWN Cancer Genome Atlas Research Network
Jul 2, 2009·The Journal of Biological Chemistry·Melanie A McGillC Jane McGlade
Oct 2, 2009·Breast Cancer Research and Treatment·Karin RennstamIngrid Hedenfalk
Feb 13, 2010·Neuro-oncology·Howard ColmanKen Aldape
Apr 14, 2010·Cancer Cell·Ruihuan ChenHeidi S Phillips
Jun 23, 2010·BMC Cancer·Hong Wei YangMark D Johnson
Jul 20, 2010·Nature·Takahiro ItoTannishtha Reya
Sep 21, 2010·Journal of Neuro-oncology·Aalya FatooJohn A Boockvar
Oct 14, 2010·Biochimica Et Biophysica Acta·Salvatore PecePier Paolo Di Fiore
Dec 3, 2010·Neural Development·Aldona KaraczynJoseph M Verdi
Jan 5, 2011·Frontiers in Bioscience (Elite Edition)·Christoph P Beier, Dagmar Beier
Jan 12, 2011·Proceedings of the National Academy of Sciences of the United States of America·Xiaowei YanQiang Tian
Sep 13, 2011·Cancer Cell·Sista SugiartoClaudia Petritsch
Sep 24, 2011·Experimental Cell Research·Philipp EuskirchenHrvoje Miletic

❮ Previous
Next ❯

Citations

Dec 5, 2012·BMC Medical Genomics·Ahmed SadequeSandra L Rodriguez-Zas
Jun 19, 2013·Cellular and Molecular Life Sciences : CMLS·Sandra Gómez-LópezClaudia Petritsch
Aug 1, 2014·Stem Cells·K B Matchett, T R Lappin
May 22, 2013·Growth Factors·Panagiotis J VlachostergiosChristos N Papandreou
Oct 16, 2015·Seminars in Cancer Biology·Wenshan XuNikita Popov
Apr 18, 2015·Neural Regeneration Research·Jian-Jun SunXiao-Hui Lou
Dec 23, 2014·Translational Neuroscience·Kate Marie Lewis, Claudia Petritsch
Jan 21, 2015·Frontiers in Oncology·Marcin Teodorczyk, Mirko H H Schmidt
Jun 3, 2016·Nature·Philipp MertinsUNKNOWN NCI CPTAC
Aug 4, 2016·Expert Opinion on Therapeutic Targets·Marianna ColamaioAlfredo Fusco
Jan 23, 2018·Head & Neck·Chung-Hsien ChouShu-Chun Lin
Apr 29, 2014·World Journal of Stem Cells·Nermin Sumru BayinDimitris George Placantonakis
Dec 9, 2017·Molecular & Cellular Proteomics : MCP·Ran WeiShawn S-C Li
Feb 23, 2019·Cancers·Bethsebie Lalduhsaki SailoAjaikumar Bahulayan Kunnumakkara
Dec 5, 2018·Frontiers in Cellular Neuroscience·Valeriia GulaiaAlexander Kagansky
Jun 6, 2014·Oncotarget·Lixia WangZhiwei Wang
Mar 6, 2019·Cancers·Riccardo Bazzoni, Angela Bentivegna
Nov 1, 2018·Molecular & Cellular Proteomics : MCP·Ran WeiShawn S-C Li

❮ Previous
Next ❯

Related Concepts

Related Feeds

Allogenic & Autologous Therapies

Allogenic therapies are generated in large batches from unrelated donor tissues such as bone marrow. In contrast, autologous therapies are manufactures as a single lot from the patient being treated. Here is the latest research on allogenic and autologous therapies.