PMID- 22022427
OWN - NLM
STAT- MEDLINE
DCOM- 20120217
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 10
DP  - 2011
TI  - Notch ankyrin repeat domain variation influences leukemogenesis and Myc 
      transactivation.
PG  - e25645
LID - 10.1371/journal.pone.0025645 [doi]
LID - e25645
AB  - BACKGROUND: 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. PRINCIPAL FINDINGS: 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. 
      CONCLUSIONS/SIGNIFICANCE: 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.
FAU - Aster, Jon C
AU  - Aster JC
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 
      United States of America. jaster@rics.bwh.harvard.edu
FAU - Bodnar, Nick
AU  - Bodnar N
FAU - Xu, Lanwei
AU  - Xu L
FAU - Karnell, Fredrick
AU  - Karnell F
FAU - Milholland, John M
AU  - Milholland JM
FAU - Maillard, Ivan
AU  - Maillard I
FAU - Histen, Gavin
AU  - Histen G
FAU - Nam, Yunsun
AU  - Nam Y
FAU - Blacklow, Stephen C
AU  - Blacklow SC
FAU - Pear, Warren S
AU  - Pear WS
LA  - eng
GR  - R01 CA092433/CA/NCI NIH HHS/United States
GR  - T32 CA009140/CA/NCI NIH HHS/United States
GR  - T32 GM007753/GM/NIGMS NIH HHS/United States
GR  - T32 CA09140/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111013
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Peptides)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Receptors, Notch)
RN  - 0 (Recombinant Proteins)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
SB  - IM
MH  - Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
MH  - Animals
MH  - *Ankyrin Repeat
MH  - Biophysical Phenomena/drug effects
MH  - Bone Marrow Transplantation
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Transformation, Neoplastic/drug effects/*pathology
MH  - *Genetic Variation/drug effects
MH  - Humans
MH  - Mice
MH  - Organ Culture Techniques
MH  - Peptides/chemistry/metabolism
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology
MH  - Protease Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-myc/*genetics/metabolism
MH  - Receptors, Notch/*chemistry/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Structure-Activity Relationship
MH  - T-Lymphocytes/drug effects/metabolism/pathology
MH  - Thymocytes/drug effects/metabolism/pathology
MH  - Transcriptional Activation/drug effects/*genetics
MH  - Transduction, Genetic
PMC - PMC3192765
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/10/25 06:00
MHDA- 2012/02/18 06:00
PMCR- 2011/10/13
CRDT- 2011/10/25 06:00
PHST- 2011/07/28 00:00 [received]
PHST- 2011/09/07 00:00 [accepted]
PHST- 2011/10/25 06:00 [entrez]
PHST- 2011/10/25 06:00 [pubmed]
PHST- 2012/02/18 06:00 [medline]
PHST- 2011/10/13 00:00 [pmc-release]
AID - PONE-D-11-15229 [pii]
AID - 10.1371/journal.pone.0025645 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(10):e25645. doi: 10.1371/journal.pone.0025645. Epub 2011 Oct 13.