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Notch Signaling in Human Neuroblastoma Cells

Stockhausen, Marie LU (2005) In Lund University Faculty of Medicine Doctoral Dissertation Series
Abstract
Neuroblastoma is a childhood tumor derived from the sympathetic nervous system (SNS). It is believed that the tumors arise from cells halted in their differentiation and due to their immature phenotype; they express proteins normally only detected during embryogenesis. One such protein is Hash-1, which is required for formation of the SNS. Hash-1 is a component of the Notch signaling cascade, which is involved in many cell fate decisions. In general, Notch activity maintains a pool of undifferentiated cells and dysregulated Notch signaling has been linked to development of several cancers. It has been shown that the Notch cascade is transiently induced during neuroblastoma cell differentiation in vitro and that persistent Notch expression... (More)
Neuroblastoma is a childhood tumor derived from the sympathetic nervous system (SNS). It is believed that the tumors arise from cells halted in their differentiation and due to their immature phenotype; they express proteins normally only detected during embryogenesis. One such protein is Hash-1, which is required for formation of the SNS. Hash-1 is a component of the Notch signaling cascade, which is involved in many cell fate decisions. In general, Notch activity maintains a pool of undifferentiated cells and dysregulated Notch signaling has been linked to development of several cancers. It has been shown that the Notch cascade is transiently induced during neuroblastoma cell differentiation in vitro and that persistent Notch expression inhibits this differentiation. These observations imply a role for Notch signaling in the blocked differentiation of neuroblastoma cells. In addition, neuroblastoma cells exposed to hypoxia, a common event of solid tumors, dedifferentiate. During this process, components of the Notch signaling cascade are up regulated. In this thesis we show that Hash-1 interacts with ubiquilin-1, a protein involved in protecting proteins from degradation. In addition, we show that valproic acid (VPA) induces differentiation of neuroblastoma cells by modulation of the Notch signaling cascade. Aberrant signaling through the EGF receptor is involved in the genesis of some human cancers. Several reports have shown cross talk between EGFR signaling and the Notch cascade. We show here that the Notch target Hes-1 can be directly regulated by Ras/MAPK signaling at both normoxia and hypoxia, without the activation of Notch receptors. (Less)
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author
supervisor
opponent
  • Professor Versteeg, Rogier, Department of Human Genetics, University of Amsterdam, The Netherlands
organization
publishing date
type
Thesis
publication status
published
subject
keywords
oncology, Hes-1, Medicin (människa och djur), Medicine (human and vertebrates), hypoxia, TGF-alpha, EGFR, ERK1/2, Ras/MAPK, differentiation, valproic acid, ubiquilin-1, neuroblastoma, Hash-1, Cytologi, onkologi, cancer, cancerology, Cytology, Notch
in
Lund University Faculty of Medicine Doctoral Dissertation Series
pages
106 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Main Lecture Hall, Pathology Building, Entrance 78, 2nd floor, Malmö University Hospital, Malmö
defense date
2005-09-16 09:15
ISSN
1652-8220
ISBN
91-85439-68-1
language
English
LU publication?
yes
id
f9f7273b-4d37-4247-b9e4-2fbf08f4a6bb (old id 545191)
date added to LUP
2007-09-25 11:21:38
date last changed
2016-09-19 08:44:53
@phdthesis{f9f7273b-4d37-4247-b9e4-2fbf08f4a6bb,
  abstract     = {Neuroblastoma is a childhood tumor derived from the sympathetic nervous system (SNS). It is believed that the tumors arise from cells halted in their differentiation and due to their immature phenotype; they express proteins normally only detected during embryogenesis. One such protein is Hash-1, which is required for formation of the SNS. Hash-1 is a component of the Notch signaling cascade, which is involved in many cell fate decisions. In general, Notch activity maintains a pool of undifferentiated cells and dysregulated Notch signaling has been linked to development of several cancers. It has been shown that the Notch cascade is transiently induced during neuroblastoma cell differentiation in vitro and that persistent Notch expression inhibits this differentiation. These observations imply a role for Notch signaling in the blocked differentiation of neuroblastoma cells. In addition, neuroblastoma cells exposed to hypoxia, a common event of solid tumors, dedifferentiate. During this process, components of the Notch signaling cascade are up regulated. In this thesis we show that Hash-1 interacts with ubiquilin-1, a protein involved in protecting proteins from degradation. In addition, we show that valproic acid (VPA) induces differentiation of neuroblastoma cells by modulation of the Notch signaling cascade. Aberrant signaling through the EGF receptor is involved in the genesis of some human cancers. Several reports have shown cross talk between EGFR signaling and the Notch cascade. We show here that the Notch target Hes-1 can be directly regulated by Ras/MAPK signaling at both normoxia and hypoxia, without the activation of Notch receptors.},
  author       = {Stockhausen, Marie},
  isbn         = {91-85439-68-1},
  issn         = {1652-8220},
  keyword      = {oncology,Hes-1,Medicin (människa och djur),Medicine (human and vertebrates),hypoxia,TGF-alpha,EGFR,ERK1/2,Ras/MAPK,differentiation,valproic acid,ubiquilin-1,neuroblastoma,Hash-1,Cytologi,onkologi,cancer,cancerology,Cytology,Notch},
  language     = {eng},
  pages        = {106},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Notch Signaling in Human Neuroblastoma Cells},
  year         = {2005},
}