Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation.
The functional interchangeability of mammalian Notch receptors (Notch1-4) in normal and pathophysiologic contexts such as cancer is unsettled. We used complementary in vivo, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3192765?pdf=render |
| _version_ | 1811281765592989696 |
|---|---|
| author | Jon C Aster Nick Bodnar Lanwei Xu Fredrick Karnell John M Milholland Ivan Maillard Gavin Histen Yunsun Nam Stephen C Blacklow Warren S Pear |
| author_facet | Jon C Aster Nick Bodnar Lanwei Xu Fredrick Karnell John M Milholland Ivan Maillard Gavin Histen Yunsun Nam Stephen C Blacklow Warren S Pear |
| author_sort | Jon C Aster |
| collection | DOAJ |
| description | The functional interchangeability of mammalian Notch receptors (Notch1-4) in normal and pathophysiologic contexts such as cancer is unsettled. We used complementary in vivo, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival.We find that the activated intracellular domains of Notch1-4 (ICN1-4) all support T cell development in mice and thymic organ culture. However, unlike ICN1-3, ICN4 fails to induce T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and is unable to rescue the growth of Notch1-dependent T-ALL cell lines. The ICN4 phenotype is mimicked by weak gain-of-function forms of Notch1, suggesting that it stems from a failure to transactivate one or more critical target genes above a necessary threshold. Experiments with chimeric receptors demonstrate that the Notch ankyrin repeat domains differ in their leukemogenic potential, and that this difference correlates with activation of Myc, a direct Notch target that has an important role in Notch-associated T-ALL.We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis. |
| first_indexed | 2024-04-13T01:39:31Z |
| format | Article |
| id | doaj.art-3613db6e838241a1a8c60558210c4dbf |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T01:39:31Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3613db6e838241a1a8c60558210c4dbf2022-12-22T03:08:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01610e2564510.1371/journal.pone.0025645Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation.Jon C AsterNick BodnarLanwei XuFredrick KarnellJohn M MilhollandIvan MaillardGavin HistenYunsun NamStephen C BlacklowWarren S PearThe functional interchangeability of mammalian Notch receptors (Notch1-4) in normal and pathophysiologic contexts such as cancer is unsettled. We used complementary in vivo, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival.We find that the activated intracellular domains of Notch1-4 (ICN1-4) all support T cell development in mice and thymic organ culture. However, unlike ICN1-3, ICN4 fails to induce T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and is unable to rescue the growth of Notch1-dependent T-ALL cell lines. The ICN4 phenotype is mimicked by weak gain-of-function forms of Notch1, suggesting that it stems from a failure to transactivate one or more critical target genes above a necessary threshold. Experiments with chimeric receptors demonstrate that the Notch ankyrin repeat domains differ in their leukemogenic potential, and that this difference correlates with activation of Myc, a direct Notch target that has an important role in Notch-associated T-ALL.We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis.http://europepmc.org/articles/PMC3192765?pdf=render |
| spellingShingle | Jon C Aster Nick Bodnar Lanwei Xu Fredrick Karnell John M Milholland Ivan Maillard Gavin Histen Yunsun Nam Stephen C Blacklow Warren S Pear Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. PLoS ONE |
| title | Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. |
| title_full | Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. |
| title_fullStr | Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. |
| title_full_unstemmed | Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. |
| title_short | Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. |
| title_sort | notch ankyrin repeat domain variation influences leukemogenesis and myc transactivation |
| url | http://europepmc.org/articles/PMC3192765?pdf=render |
| work_keys_str_mv | AT joncaster notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT nickbodnar notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT lanweixu notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT fredrickkarnell notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT johnmmilholland notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT ivanmaillard notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT gavinhisten notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT yunsunnam notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT stephencblacklow notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation AT warrenspear notchankyrinrepeatdomainvariationinfluencesleukemogenesisandmyctransactivation |