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Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis

Bellodi, Cristian LU ; Krasnykh, Olya; Haynes, Nikesha; Theodoropoulou, Marily; Peng, Guang; Montanaro, Lorenzo and Ruggero, Davide (2010) In Cancer Research 70(14). p.35-6026
Abstract

Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27... (More)

Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27 heterozygous mice. Using a new bioluminescent mouse model, we monitored p27 translation in vivo and show that p27 IRES-mediated translation is reduced in the pituitary of DKC1 hypomorphic mice (DKC1(m)). Furthermore, we show that DKC1 has a critical role in regulating the assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. An analysis of human tumors identified a novel mutation of DKC1 (DKC1(S485G)) in a human pituitary adenoma. We show that this specific amino acid substitution significantly alters DKC1 stability/pseudouridylation activity, and this correlates with reductions in p27 protein levels. Furthermore, DKC1(S485G) mutation does not alter telomerase RNA levels. Altogether, these findings show that genetic alterations in DKC1 could contribute to tumorigenesis associated with somatic cancers and establish a critical role for DKC1 in tumor suppression, at least in part, through translational control of p27.

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author
publishing date
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Contribution to journal
publication status
published
subject
keywords
Animals, Cell Cycle Proteins, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p27, Female, Genes, Tumor Suppressor, Humans, Mice, Mice, Transgenic, Middle Aged, Mutation, Nuclear Proteins, Pituitary Neoplasms, Translocation, Genetic
in
Cancer Research
volume
70
issue
14
pages
10 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:77955044544
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-09-4730
language
English
LU publication?
no
id
b5161b51-af10-4220-b91b-a8eee28a1c27
date added to LUP
2016-04-29 15:51:04
date last changed
2017-02-05 04:49:30
@article{b5161b51-af10-4220-b91b-a8eee28a1c27,
  abstract     = {<p>Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27 heterozygous mice. Using a new bioluminescent mouse model, we monitored p27 translation in vivo and show that p27 IRES-mediated translation is reduced in the pituitary of DKC1 hypomorphic mice (DKC1(m)). Furthermore, we show that DKC1 has a critical role in regulating the assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. An analysis of human tumors identified a novel mutation of DKC1 (DKC1(S485G)) in a human pituitary adenoma. We show that this specific amino acid substitution significantly alters DKC1 stability/pseudouridylation activity, and this correlates with reductions in p27 protein levels. Furthermore, DKC1(S485G) mutation does not alter telomerase RNA levels. Altogether, these findings show that genetic alterations in DKC1 could contribute to tumorigenesis associated with somatic cancers and establish a critical role for DKC1 in tumor suppression, at least in part, through translational control of p27.</p>},
  author       = {Bellodi, Cristian and Krasnykh, Olya and Haynes, Nikesha and Theodoropoulou, Marily and Peng, Guang and Montanaro, Lorenzo and Ruggero, Davide},
  issn         = {1538-7445},
  keyword      = {Animals,Cell Cycle Proteins,Cell Transformation, Neoplastic,Cyclin-Dependent Kinase Inhibitor p27,Female,Genes, Tumor Suppressor,Humans,Mice,Mice, Transgenic,Middle Aged,Mutation,Nuclear Proteins,Pituitary Neoplasms,Translocation, Genetic},
  language     = {eng},
  month        = {07},
  number       = {14},
  pages        = {35--6026},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-09-4730},
  volume       = {70},
  year         = {2010},
}