PMID- 22496623
OWN - NLM
STAT- MEDLINE
DCOM- 20120807
LR  - 20211021
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 14
IP  - 3
DP  - 2012 Mar
TI  - Rare Drosha splice variants are deficient in microRNA processing but do not 
      affect general microRNA expression in cancer cells.
PG  - 238-48
AB  - Drosha is a key enzyme in microRNA biogenesis, generating the precursor miRNA 
      (pre-miRNA) by excising the stem-loop embedded in the primary transcripts 
      (pri-miRNA). The specificity for the pri-miRNAs and determination of the cleavage 
      site are provided by its binding partner DGCR8, which is necessary for efficient 
      processing. The crucial Drosha domains for pri-miRNA cleavage are the middle 
      part, the two enzymatic RNase III domains (RIIID), and the dsRNA binding domain 
      (dsRBD) in the C-terminus. Here, we identify alternatively spliced transcripts in 
      human melanoma and NT2 cell lines, encoding C-terminally truncated Drosha 
      proteins lacking part of the RIIIDb and the entire dsRBD. Proteins generated from 
      these alternative splice variants fail to bind to DGCR8 but still interact with 
      Ewing sarcoma protein (EWS). In vitro as well as in vivo, the Drosha splice 
      variants are deficient in pri-miRNA processing. However, the aberrant transcripts 
      in melanoma cells do not consistently reduce mature miRNA levels compared with 
      melanoma cell lines lacking those splice variants, possibly owing to their 
      limited abundance. Our findings show that alternative processing-deficient Drosha 
      splice variants exist in melanoma cells. In elevated amounts, these alternatively 
      spliced transcripts could provide one potential mechanism accounting for the 
      deregulation of miRNAs in cancer cells. On the basis of our results, the search 
      for alternative inactive splice variants might be fruitful in different tumor 
      entities to unravel the molecular basis of the previously observed decreased 
      microRNA processing efficiency in cancer.
CI  - Copyright (c) 2012 Neoplasia Press, Inc.
FAU - Grund, Stefanie E
AU  - Grund SE
AD  - Helmholtz-University-Group Molecular RNA Biology & Cancer, German Cancer Research 
      Center DKFZ & Institute of Pathology, University of Heidelberg, Heidelberg, 
      Germany.
FAU - Polycarpou-Schwarz, Maria
AU  - Polycarpou-Schwarz M
FAU - Luo, Chonglin
AU  - Luo C
FAU - Eichmuller, Stefan B
AU  - Eichmuller SB
FAU - Diederichs, Sven
AU  - Diederichs S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (DGCR8 protein, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Proteins)
RN  - 0 (RNA-Binding Proteins)
RN  - EC 3.1.26.3 (DROSHA protein, human)
RN  - EC 3.1.26.3 (Ribonuclease III)
SB  - IM
MH  - *Alternative Splicing
MH  - Amino Acid Sequence
MH  - Cell Line
MH  - Cytoplasm/metabolism
MH  - Gene Order
MH  - Humans
MH  - MicroRNAs/*metabolism
MH  - Molecular Sequence Data
MH  - Neoplasms/*genetics/metabolism
MH  - Protein Binding
MH  - Proteins/metabolism
MH  - RNA-Binding Proteins
MH  - Ribonuclease III/chemistry/*genetics/metabolism
MH  - Sequence Alignment
PMC - PMC3323901
EDAT- 2012/04/13 06:00
MHDA- 2012/08/08 06:00
PMCR- 2012/03/01
CRDT- 2012/04/13 06:00
PHST- 2011/11/14 00:00 [received]
PHST- 2012/02/11 00:00 [revised]
PHST- 2012/02/13 00:00 [accepted]
PHST- 2012/04/13 06:00 [entrez]
PHST- 2012/04/13 06:00 [pubmed]
PHST- 2012/08/08 06:00 [medline]
PHST- 2012/03/01 00:00 [pmc-release]
AID - 111586 [pii]
AID - 10.1593/neo.111586 [doi]
PST - ppublish
SO  - Neoplasia. 2012 Mar;14(3):238-48. doi: 10.1593/neo.111586.