Dicerがやられると癌になる？？！！？

出るべくしてでた論文ではあるが、Dicerの構成要素にTARBP2 (TAR RNA-binding protein 2)というのがあって、こいつがframeshiftしている癌があるのだそうだ。そうするとmiRNA がsystematicにうまく行かなくなって・・・・というのが論旨。この論文の中身はぜひぜひ読みたい。臨床癌でどれくらい関係しているのか知りたい。続編が続々出て、結局？？？になりそうな予感もするが。

ところで著者の一人山本博幸氏は札幌医大第一内科の講師だが、スペイン人に混じって健闘しているなあ。学会でよくお目にかかるヒトだ。

Nature Genetics 41, 365 - 370 (2009)

Published online: 15 February 2009 |

A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function

Sonia A Melo¹, Santiago Ropero¹, Catia Moutinho¹, Lauri A Aaltonen², Hiroyuki Yamamoto³, George A Calin⁴, Simona Rossi⁴, Agustin F Fernandez¹, Fatima Carneiro⁵, Carla Oliveira⁵, Bibiana Ferreira¹, Chang-Gong Liu⁴, Alberto Villanueva⁶, Gabriel Capella⁶, Simo Schwartz Jr⁷, Ramin Shiekhattar^8,9 & Manel Esteller^1,9,10

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting messenger RNA (mRNA) transcripts. Recently, a miRNA expression profile of human tumors has been characterized by an overall miRNA downregulation^{1, 2, 3}. Explanations for this observation include a failure of miRNA post-transcriptional regulation⁴, transcriptional silencing associated with hypermethylation of CpG island promoters^{5, 6, 7} and miRNA transcriptional repression by oncogenic factors⁸. Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation⁹. However, no loss-of-function genetic alterations in the genes encoding these proteins have been reported. Here we have identified truncating mutations in TARBP2 (TAR RNA-binding protein 2), encoding an integral component of a DICER1-containing complex^{10, 11}, in sporadic and hereditary carcinomas with microsatellite instability^{12, 13, 14}. The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs. The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth. Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs.