Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis.
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.
Bellodi
Cristian
C
School of Medicine and Department of Urology, Helen Diller Family Comprehensive Center, University of California, San Francisco, California 94158, USA.
Krasnykh
Olya
O
Haynes
Nikesha
N
Theodoropoulou
Marily
M
Peng
Guang
G
Montanaro
Lorenzo
L
Ruggero
Davide
D
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic
D018797:Cell Cycle Proteins; C510431:Dkc1 protein, mouse; D009687:Nuclear Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27