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Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency

Aleksandra Zwolinska UGent, A Heagle Whiting, Chantal Beekman UGent, JM Sedivy and Jean-Christophe Marine UGent (2012) ONCOGENE. 31(28). p.3311-3321
abstract
Nucleostemin (NS), a nucleolar GTPase, is highly expressed in stem/progenitor cells and in most cancer cells. However, little is known about the regulation of its expression. Here, we identify the NS gene as a novel direct transcriptional target of the c-Myc oncoprotein. We show that Myc overexpression enhances NS transcription in cultured cells and in pre-neoplastic B cells from El-myc transgenic mice. Consistent with NS being downstream of Myc, NS expression parallels that of Myc in a large panel of human cancer cell lines. Using chromatin immunoprecipitation we show that c-Myc binds to a well-conserved E-box in the NS promoter. Critically, we show NS haploinsufficiency profoundly delays Myc-induced cancer formation in vivo. NS+/- El-myc transgenic mice have much slower rates of B-cell lymphoma development, with life spans twice that of their wild-type littermates. Moreover, we demonstrate that NS is essential for the proliferation of Myc-overexpressing cells in cultured cells and in vivo: impaired lymphoma development was associated with a drastic decrease of c-Myc-induced proliferation of pre-tumoural B cells. Finally, we provide evidence that in cell culture NS controls cell proliferation independently of p53 and that NS haploinsufficiency significantly delays lymphomagenesis in p53-deficient mice. Together these data indicate that NS functions downstream of Myc as a rate-limiting regulator of cell proliferation and transformation, independently from its putative role within the p53 pathway. Targeting NS is therefore expected to compromise early tumour development irrespectively of the p53 status.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
lymphoma, p53, c-Myc, nucleostemin, transgenic mice, TARGETED HOMOLOGOUS RECOMBINATION, RIBOSOMAL-PROTEIN L23, CELL-CYCLE ARREST, C-MYC, STEM-CELLS, IN-VIVO, GENE-EXPRESSION, DNA-DAMAGE, TRANSCRIPTIONAL REGULATION, INDUCED LYMPHOMAGENESIS
journal title
ONCOGENE
Oncogene
volume
31
issue
28
pages
3311 - 3321
Web of Science type
Article
Web of Science id
000306367600001
JCR category
GENETICS & HEREDITY
JCR impact factor
7.357 (2012)
JCR rank
15/161 (2012)
JCR quartile
1 (2012)
ISSN
0950-9232
DOI
10.1038/onc.2011.507
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2984529
handle
http://hdl.handle.net/1854/LU-2984529
date created
2012-09-10 17:19:07
date last changed
2012-09-11 09:13:31
@article{2984529,
  abstract     = {Nucleostemin (NS), a nucleolar GTPase, is highly expressed in stem/progenitor cells and in most cancer cells. However, little is known about the regulation of its expression. Here, we identify the NS gene as a novel direct transcriptional target of the c-Myc oncoprotein. We show that Myc overexpression enhances NS transcription in cultured cells and in pre-neoplastic B cells from El-myc transgenic mice. Consistent with NS being downstream of Myc, NS expression parallels that of Myc in a large panel of human cancer cell lines. Using chromatin immunoprecipitation we show that c-Myc binds to a well-conserved E-box in the NS promoter. Critically, we show NS haploinsufficiency profoundly delays Myc-induced cancer formation in vivo. NS+/- El-myc transgenic mice have much slower rates of B-cell lymphoma development, with life spans twice that of their wild-type littermates. Moreover, we demonstrate that NS is essential for the proliferation of Myc-overexpressing cells in cultured cells and in vivo: impaired lymphoma development was associated with a drastic decrease of c-Myc-induced proliferation of pre-tumoural B cells. Finally, we provide evidence that in cell culture NS controls cell proliferation independently of p53 and that NS haploinsufficiency significantly delays lymphomagenesis in p53-deficient mice. Together these data indicate that NS functions downstream of Myc as a rate-limiting regulator of cell proliferation and transformation, independently from its putative role within the p53 pathway. Targeting NS is therefore expected to compromise early tumour development irrespectively of the p53 status.},
  author       = {Zwolinska, Aleksandra and Whiting, A Heagle and Beekman, Chantal and Sedivy, JM and Marine, Jean-Christophe},
  issn         = {0950-9232},
  journal      = {ONCOGENE},
  keyword      = {lymphoma,p53,c-Myc,nucleostemin,transgenic mice,TARGETED HOMOLOGOUS RECOMBINATION,RIBOSOMAL-PROTEIN L23,CELL-CYCLE ARREST,C-MYC,STEM-CELLS,IN-VIVO,GENE-EXPRESSION,DNA-DAMAGE,TRANSCRIPTIONAL REGULATION,INDUCED LYMPHOMAGENESIS},
  language     = {eng},
  number       = {28},
  pages        = {3311--3321},
  title        = {Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency},
  url          = {http://dx.doi.org/10.1038/onc.2011.507},
  volume       = {31},
  year         = {2012},
}

Chicago
Zwolinska, Aleksandra, A Heagle Whiting, Chantal Beekman, JM Sedivy, and Jean-Christophe Marine. 2012. “Suppression of Myc Oncogenic Activity by Nucleostemin Haploinsufficiency.” Oncogene 31 (28): 3311–3321.
APA
Zwolinska, A., Whiting, A. H., Beekman, C., Sedivy, J., & Marine, J.-C. (2012). Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency. ONCOGENE, 31(28), 3311–3321.
Vancouver
1.
Zwolinska A, Whiting AH, Beekman C, Sedivy J, Marine J-C. Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency. ONCOGENE. 2012;31(28):3311–21.
MLA
Zwolinska, Aleksandra, A Heagle Whiting, Chantal Beekman, et al. “Suppression of Myc Oncogenic Activity by Nucleostemin Haploinsufficiency.” ONCOGENE 31.28 (2012): 3311–3321. Print.