PMID- 22666390
OWN - NLM
STAT- MEDLINE
DCOM- 20121029
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 5
DP  - 2012
TI  - Novel mechanism of action on Hedgehog signaling by a suppressor of fused carboxy 
      terminal variant.
PG  - e37761
LID - 10.1371/journal.pone.0037761 [doi]
LID - e37761
AB  - The Suppressor of Fused (SUFU) protein plays an essential role in the Hedgehog 
      (HH) signaling pathway, by regulation of the GLI transcription factors. Two major 
      isoforms of human SUFU are known, a full-length (SUFU-FL) and a carboxy-terminal 
      truncated (SUFU- DeltaC) variant. Even though SUFU- DeltaC is expressed at an equivalent 
      level as SUFU-FL in certain tissues, the function of SUFU-DeltaC and its impact on HH 
      signal transduction is still unclear. In two cell lines from rhabdomyosarcoma, a 
      tumor type associated with deregulated HH signaling, SUFU-DeltaC mRNA was expressed 
      at comparable levels as SUFU-FL mRNA, but at the protein level only low amounts 
      of SUFU-DeltaC were detectable. Heterologous expression provided support to the 
      notion that the SUFU-DeltaC protein is less stable compared to SUFU-FL. Despite this, 
      biochemical analysis revealed that SUFU-DeltaC could repress GLI2 and GLI1DeltaN, but not 
      GLI1FL, transcriptional activity to the same extent as SUFU-FL. Moreover, under 
      conditions of activated HH signaling SUFU-DeltaC was more effective than SUFU-FL in 
      inhibiting GLI1DeltaN. Importantly, co-expression with GLI1FL indicated that SUFU-DeltaC 
      but not SUFU-FL reduced the protein levels of GLI1FL. Additionally, confocal 
      microscopy revealed a co-localization of GLI1FL with SUFU-DeltaC but not SUFU-FL in 
      aggregate structures. Moreover, specific siRNA mediated knock-down of SUFU-DeltaC 
      resulted in up-regulation of the protein levels of GLI1FL and the HH signaling 
      target genes PTCH1 and HHIP. Our results are therefore suggesting the presence of 
      novel regulatory controls in the HH signaling pathway, which are elicited by the 
      distinct mechanism of action of the two alternative spliced SUFU proteins.
FAU - Tostar, Ulrica
AU  - Tostar U
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
FAU - Finta, Csaba
AU  - Finta C
FAU - Rahman, Mohammed Ferdous-Ur
AU  - Rahman MF
FAU - Shimokawa, Takashi
AU  - Shimokawa T
FAU - Zaphiropoulos, Peter G
AU  - Zaphiropoulos PG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120529
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Repressor Proteins)
RN  - 0 (SUFU protein, human)
RN  - 0 (Sufu protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Zinc Finger Protein GLI1)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Gene Knockdown Techniques
MH  - Hedgehog Proteins/*metabolism
MH  - Humans
MH  - Intracellular Space/metabolism
MH  - Mice
MH  - Mutation
MH  - Oncogene Proteins/genetics/metabolism
MH  - Protein Isoforms/chemistry/deficiency/genetics/metabolism
MH  - Protein Transport
MH  - Repressor Proteins/*chemistry/deficiency/genetics/*metabolism
MH  - *Signal Transduction
MH  - Trans-Activators/genetics/metabolism
MH  - Up-Regulation
MH  - Zinc Finger Protein GLI1
PMC - PMC3362617
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/06/06 06:00
MHDA- 2012/10/30 06:00
PMCR- 2012/05/29
CRDT- 2012/06/06 06:00
PHST- 2011/11/07 00:00 [received]
PHST- 2012/04/24 00:00 [accepted]
PHST- 2012/06/06 06:00 [entrez]
PHST- 2012/06/06 06:00 [pubmed]
PHST- 2012/10/30 06:00 [medline]
PHST- 2012/05/29 00:00 [pmc-release]
AID - PONE-D-11-22335 [pii]
AID - 10.1371/journal.pone.0037761 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(5):e37761. doi: 10.1371/journal.pone.0037761. Epub 2012 May 29.