The new LAW of microRNA-mediated gene silencing: implications for lung cancer development

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• Dr Tyson V. Sharp, School of Biomedical Sciences, University of Nottingham
• Tuesday 15 December 2009, 12:00-13:00
• CRI Lecture Theatre.

If you have a question about this talk, please contact Mala Jayasundera.

We have previously reported the tumour suppressive function of LIMD1 and recently shown that LIMD1 is a bona fide tumour suppressor gene, the loss of which contributes to lung cancer development and differential subcellular expression correlates with poor prognosis in breast cancer (1, 2). Following on from these studies we performed a series of experiments to characterize LIMD1 localisation and observed considerable localisation of LIMD1 within the cytoplasm in discrete punctate bodies/foci. However, the identity or biological relevance of these cytoplasmic foci was unknown.

Herein we report the identity of the LIMD1 cytoplasmic foci as mammalian mRNA processing (P) bodies (herein referred to as P-bodies), cytoplasmic compartments involved in miRNA mediated mRNA translation inhibition, degradation and storage (3-9). Biochemical analysis revealed that LIMD1 localises to a ribonucleoprotein complex with other P-body associated proteins eIF4E, RCK /p54, Ago2, and DCP2 . Similar analysis with other Zyxin family members reveal a novel family of LIM domain containing proteins (LIMD1, Ajuba and WTIP ; LAW proteins) that function in the miRNA mediated gene silencing pathway and specifically associate with P-bodies. Expression of a LIMD1 deletion mutant or depletion of endogenous LIMD1 resulted in specific loss of miRNA-mediated gene silencing and disrupted P-body formation. We also show that LIMD1 associates with the m7GTP mRNA cap structure through a specific and direct interaction with eIF4E, thereby enabling microRNA processing by acting as an essential molecular bridge linking the cap structure to the miRISC complex bound to the 3’-UTR. siRNA mediated knockdown of LAW proteins resulted in a specific inhibition of miRNA but not siRNA-mediated gene silencing.

The function of LIMD1 in miRNA silencing is consistent with its tumour suppressive role in cancer development, in a similar manner to that described for other key components of the miRNA processing pathway, such as Dicer, DGCR8 , Drosha, Lin28, TRBP and more recently p53 (10-13).

Reference List

1.     T. V. Sharp et al., Proc. Natl. Acad. Sci. U. S. A 105, 19932 (2008).
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4.     A. Jakymiw et al., Nat. Cell Biol. 7, 1267 (2005).
5.     A. B. Shyu, M. F. Wilkinson, H. A. van, EMBO J. 27, 471 (2008).
6.     N. Kedersha, P. Anderson, Methods Enzymol. 431, 61 (2007).
7.     R. Parker, U. Sheth, Mol. Cell 25, 635 (2007).
8.     A. Eulalio, I. Behm-Ansmant, E. Izaurralde, Nat. Rev. Mol. Cell Biol. 8, 9 (2007).
9.     T. M. Franks, J. Lykke-Andersen, Mol. Cell 32, 605 (2008).
10.     M. S. Kumar, J. Lu, K. L. Mercer, T. R. Golub, T. Jacks, Nat. Genet. 39, 673 (2007).
11.     S. A. Melo et al., Nat. Genet. 41, 365 (2009).
12.     H. I. Suzuki et al., Nature 460, 529 (2009).
13.     S. R. Viswanathan et al., Nat. Genet. 41, 843 (2009).

This talk is part of the Cambridge Oncology Seminar Series series.

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