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Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation

David Nittner UGent, Irina Lambertz UGent, Frederic Clermont, Pieter Mestdagh UGent, Corinna Köhler, Søren Jensby Nielsen, Aart Jochemsen, Franki Speleman UGent, Jo Vandesompele UGent and Michael A Dyer, et al. (2012) NATURE CELL BIOLOGY. 14(9). p.958-965
abstract
Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells(1). This approach may help over come the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1,2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MOUSE RETINA, IN-VIVO, PATHWAY, TUMORIGENESIS, EXPRESSION, CLUSTER, TUMOR
journal title
NATURE CELL BIOLOGY
Nat. Cell Biol.
volume
14
issue
9
pages
958 - 965
Web of Science type
Article
Web of Science id
000308668600012
JCR category
CELL BIOLOGY
JCR impact factor
20.761 (2012)
JCR rank
6/181 (2012)
JCR quartile
1 (2012)
ISSN
1465-7392
DOI
10.1038/ncb2556
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3021992
handle
http://hdl.handle.net/1854/LU-3021992
date created
2012-10-11 09:18:59
date last changed
2012-10-12 09:22:05
@article{3021992,
  abstract     = {Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells(1). This approach may help over come the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1,2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.},
  author       = {Nittner, David and Lambertz, Irina and Clermont, Frederic and Mestdagh, Pieter and K{\"o}hler, Corinna and Nielsen, S{\o}ren Jensby and Jochemsen, Aart and Speleman, Franki and Vandesompele, Jo and Dyer, Michael A and Schramm, Alexander and Schulte, Johannes H and Marine, Jean-Christophe},
  issn         = {1465-7392},
  journal      = {NATURE CELL BIOLOGY},
  keyword      = {MOUSE RETINA,IN-VIVO,PATHWAY,TUMORIGENESIS,EXPRESSION,CLUSTER,TUMOR},
  language     = {eng},
  number       = {9},
  pages        = {958--965},
  title        = {Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation},
  url          = {http://dx.doi.org/10.1038/ncb2556},
  volume       = {14},
  year         = {2012},
}

Chicago
Nittner, David, Irina Lambertz, Frederic Clermont, Pieter Mestdagh, Corinna Köhler, Søren Jensby Nielsen, Aart Jochemsen, et al. 2012. “Synthetic Lethality Between Rb, P53 and Dicer or miR-17-92 in Retinal Progenitors Suppresses Retinoblastoma Formation.” Nature Cell Biology 14 (9): 958–965.
APA
Nittner, D., Lambertz, I., Clermont, F., Mestdagh, P., Köhler, C., Nielsen, S. J., Jochemsen, A., et al. (2012). Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation. NATURE CELL BIOLOGY, 14(9), 958–965.
Vancouver
1.
Nittner D, Lambertz I, Clermont F, Mestdagh P, Köhler C, Nielsen SJ, et al. Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation. NATURE CELL BIOLOGY. 2012;14(9):958–65.
MLA
Nittner, David, Irina Lambertz, Frederic Clermont, et al. “Synthetic Lethality Between Rb, P53 and Dicer or miR-17-92 in Retinal Progenitors Suppresses Retinoblastoma Formation.” NATURE CELL BIOLOGY 14.9 (2012): 958–965. Print.