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The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma

Revet, Ingrid; Huizenga, Gerda; Chan, Alvin; Koster, Jan; Volckmann, Richard; van Sluis, Peter; Øra, Ingrid LU ; Versteeg, Rogier and Geerts, Dirk (2008) In Experimental Cell Research 314(4). p.707-719
Abstract
Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro-array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1. In addition, the proneural gene NEUROD1 was... (More)
Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro-array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1. In addition, the proneural gene NEUROD1 was down-regulated. Western blot analysis showed that MSX1 induction caused cleavage of the NOTCH3 protein to its activated form, further confirming activation of the Delta-Notch pathway. These experiments describe for the first time regulation of the Delta-Notch pathway by MSX1, and connect these genes to the PHOX2B oncogene, indicative of a role in neuroblastoma biology. Affymetrix micro-array analysis of a neuroblastic tumour series consisting of neuroblastomas and the more benign ganglioneuromas showed that MSX1, NOTCH3 and HEY1 are more highly expressed in ganglioneuromas. This suggests a block in differentiation of these tumours at distinct developmental stages or lineages. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Delta, Affymetrix, MSX1, Neuroblastoma, Notch, PHOX2B, Ganglioneuroma
in
Experimental Cell Research
volume
314
issue
4
pages
707 - 719
publisher
Academic Press
external identifiers
  • pmid:18201699
  • scopus:38949115590
ISSN
1090-2422
DOI
10.1016/j.yexcr.2007.12.008
language
English
LU publication?
no
id
115c1aa1-7527-4799-8f07-d3fd73d2492b (old id 1144384)
date added to LUP
2008-08-13 12:34:03
date last changed
2017-07-23 03:39:37
@article{115c1aa1-7527-4799-8f07-d3fd73d2492b,
  abstract     = {Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro-array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1. In addition, the proneural gene NEUROD1 was down-regulated. Western blot analysis showed that MSX1 induction caused cleavage of the NOTCH3 protein to its activated form, further confirming activation of the Delta-Notch pathway. These experiments describe for the first time regulation of the Delta-Notch pathway by MSX1, and connect these genes to the PHOX2B oncogene, indicative of a role in neuroblastoma biology. Affymetrix micro-array analysis of a neuroblastic tumour series consisting of neuroblastomas and the more benign ganglioneuromas showed that MSX1, NOTCH3 and HEY1 are more highly expressed in ganglioneuromas. This suggests a block in differentiation of these tumours at distinct developmental stages or lineages.},
  author       = {Revet, Ingrid and Huizenga, Gerda and Chan, Alvin and Koster, Jan and Volckmann, Richard and van Sluis, Peter and Øra, Ingrid and Versteeg, Rogier and Geerts, Dirk},
  issn         = {1090-2422},
  keyword      = {Delta,Affymetrix,MSX1,Neuroblastoma,Notch,PHOX2B,Ganglioneuroma},
  language     = {eng},
  number       = {4},
  pages        = {707--719},
  publisher    = {Academic Press},
  series       = {Experimental Cell Research},
  title        = {The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma},
  url          = {http://dx.doi.org/10.1016/j.yexcr.2007.12.008},
  volume       = {314},
  year         = {2008},
}