PMID- 18378682
OWN - NLM
STAT- MEDLINE
DCOM- 20080718
LR  - 20231213
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 21
DP  - 2008 May 23
TI  - Novel human glioma-associated oncogene 1 (GLI1) splice variants reveal distinct 
      mechanisms in the terminal transduction of the hedgehog signal.
PG  - 14345-54
LID - 10.1074/jbc.M800299200 [doi]
AB  - Hedgehog (HH) signaling is one of the key pathways with major significance for 
      embryogenesis, tumorigenesis, and stem cell maintenance. Glioma-associated 
      oncogene 1 (GLI1) is a transcription factor that acts as the terminal signaling 
      effector but also represents a pathway target gene. Here we report the 
      identification and functional properties of novel GLI1 splice variants generated 
      by skipping exons 2 and 3 and encoding an N-terminal truncated GLI1 protein 
      (GLI1DeltaN). Analysis of the GLI1DeltaN mRNAs in adult human tissues revealed 
      comparable expression levels to the full-length GLI1 (GLI1FL), whereas in tumor 
      cell lines a generally lower and more variable expression pattern was observed. 
      Furthermore, GLI1DeltaN is up-regulated by HH signaling to the same extent as 
      GLI1FL but has a weaker capacity to activate transcription. However, in specific 
      cellular contexts GLI1DeltaN may be more potent than GLI1FL in activating 
      endogenous gene expression. Moreover, the dual-specificity tyrosine 
      phosphorylation-regulated kinase 1 (Dyrk1) potentiates the transcriptional 
      activity of GLI1FL but not GLI1DeltaN. Interestingly, GLI1FL, in contrast to 
      GLI1DeltaN, is localized solely at the nucleus, in line with its increased 
      transcriptional capacity. The negative regulator of the pathway, Suppressor of 
      Fused (SUFU), elicits a cytoplasmic retention of the GLI1 isoforms, which is more 
      pronounced for GLI1FL, as this contains an N-terminal SUFU binding domain. 
      Collectively, our findings reveal that the activation mechanism of the terminal 
      transducer of the pathway, GLI1, is mediated not only by GLI1FL but also by the 
      GLI1DeltaN variant.
FAU - Shimokawa, Takashi
AU  - Shimokawa T
AD  - Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. 
      tash@biosci.ki.se
FAU - Tostar, Ulrica
AU  - Tostar U
FAU - Lauth, Matthias
AU  - Lauth M
FAU - Palaniswamy, Ramesh
AU  - Palaniswamy R
FAU - Kasper, Maria
AU  - Kasper M
FAU - Toftgard, Rune
AU  - Toftgard R
FAU - Zaphiropoulos, Peter G
AU  - Zaphiropoulos PG
LA  - eng
SI  - GENBANK/AB239136
SI  - GENBANK/AB239328
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080331
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Alternative Splicing/*genetics
MH  - Animals
MH  - Cell Line
MH  - Gene Deletion
MH  - Hedgehog Proteins/*metabolism
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Neoplasms/genetics/metabolism
MH  - Polyribosomes/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Protein-Tyrosine Kinases/metabolism
MH  - *Signal Transduction
MH  - Substrate Specificity
MH  - Transcription Factors/*genetics/*metabolism
MH  - Transcription, Genetic/genetics
MH  - Zinc Finger Protein GLI1
MH  - Dyrk Kinases
PMC - PMC2386930
EDAT- 2008/04/02 09:00
MHDA- 2008/07/19 09:00
PMCR- 2008/05/23
CRDT- 2008/04/02 09:00
PHST- 2008/04/02 09:00 [pubmed]
PHST- 2008/07/19 09:00 [medline]
PHST- 2008/04/02 09:00 [entrez]
PHST- 2008/05/23 00:00 [pmc-release]
AID - S0021-9258(20)54301-9 [pii]
AID - 14345 [pii]
AID - 10.1074/jbc.M800299200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 May 23;283(21):14345-54. doi: 10.1074/jbc.M800299200. Epub 2008 
      Mar 31.