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SUMMARY:The new LAW of microRNA-mediated gene silencing: implications for 
 lung cancer development - Dr Tyson V. Sharp\, School of Biomedical Science
 s\, University of Nottingham
DTSTART:20091215T120000Z
DTEND:20091215T130000Z
UID:TALK19421@talks.cam.ac.uk
CONTACT:Mala Jayasundera
DESCRIPTION: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 differenti
 al subcellular expression correlates with poor prognosis in breast cancer 
 (1\, 2).  Following on from these studies we performed a series of experim
 ents to characterize LIMD1 localisation and observed considerable localisa
 tion of LIMD1 within the cytoplasm in discrete punctate bodies/foci. Howev
 er\, the identity or biological relevance of these cytoplasmic foci was un
 known.\n \nHerein we report the identity of the LIMD1 cytoplasmic foci as 
 mammalian mRNA processing (P) bodies (herein referred to as P-bodies)\, cy
 toplasmic compartments involved in miRNA mediated mRNA translation inhibit
 ion\, degradation and storage (3-9). Biochemical analysis revealed that LI
 MD1 localises to a ribonucleoprotein complex with other P-body associated 
 proteins eIF4E\, RCK/p54\, Ago2\, and DCP2. Similar analysis with other Zy
 xin family members reveal a novel family of LIM domain containing proteins
  (LIMD1\, Ajuba and WTIP\; LAW proteins) that function in the miRNA mediat
 ed gene silencing pathway and specifically associate with P-bodies.  Expre
 ssion of a LIMD1 deletion mutant or depletion of endogenous LIMD1 resulted
  in specific loss of miRNA-mediated gene silencing and disrupted P-body fo
 rmation. We also show that LIMD1 associates with the m7GTP mRNA cap struct
 ure through a specific and direct interaction with eIF4E\, thereby enablin
 g microRNA processing by acting as an essential molecular bridge linking t
 he cap structure to the miRISC complex bound to the 3’-UTR. siRNA mediat
 ed knockdown of LAW proteins resulted in a specific inhibition of miRNA bu
 t not siRNA-mediated gene silencing. \n\nThe function of LIMD1 in miRNA si
 lencing is consistent with its tumour suppressive role in cancer developme
 nt\, 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).\n\nReference List\n\n	1. 	T. V. Sharp et al
 .\, Proc. Natl. Acad. Sci. U. S. A 105\, 19932 (2008).\n	2. 	I. Spendlove 
 et al.\, Int. J. Cancer 123\, 2247 (2008).\n	3. 	N. Cougot\, S. Babajko\, 
 B. Seraphin\, J. Cell Biol. 165\, 31 (2004).\n	4. 	A. Jakymiw et al.\, Nat
 . Cell Biol. 7\, 1267 (2005).\n	5. 	A. B. Shyu\, M. F. Wilkinson\, H. A. v
 an\, EMBO J. 27\, 471 (2008).\n	6. 	N. Kedersha\, P. Anderson\, Methods En
 zymol. 431\, 61 (2007).\n	7. 	R. Parker\, U. Sheth\, Mol. Cell 25\, 635 (2
 007).\n	8. 	A. Eulalio\, I. Behm-Ansmant\, E. Izaurralde\, Nat. Rev. Mol. 
 Cell Biol. 8\, 9 (2007).\n	9. 	T. M. Franks\, J. Lykke-Andersen\, Mol. Cel
 l 32\, 605 (2008).\n	10. 	M. S. Kumar\, J. Lu\, K. L. Mercer\, T. R. Golub
 \, T. Jacks\, Nat. Genet. 39\, 673 (2007).\n	11. 	S. A. Melo et al.\, Nat.
  Genet. 41\, 365 (2009).\n	12. 	H. I. Suzuki et al.\, Nature 460\, 529 (20
 09).\n	13. 	S. R. Viswanathan et al.\, Nat. Genet. 41\, 843 (2009).\n
LOCATION:CRI Lecture Theatre
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