GLI1 (glioma-associated oncogene homolog 1)

2005-03-01 Anna Dahlén , Fredrik Mertens , Nils Mandahl , Ioannis Panagopoulos Affiliation

Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden

Identity

HGNC

GLI1

LOCATION

12q13.3

LOCUSID

2735

ALIAS

GLI,PAPA8,PPD1

FUSION GENES

Show Gene Fusions

DNA/RNA

Genomic organization of the GLI1 gene.

Description

12 exons, spans approximately 12 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon is located to exon 2, and the stop codon to exon 12.

Transcription

mRNA of 3.6 kb

Proteins

Description

The open reading frame encodes a 1106 amino acid protein, with an estimated molecular weight of approximately 118 kDa. The protein contains five DNA-binding zinc fingers between amino acids 235 and 393 (encoded by exons 7-10), and a transactivating domain constituted by amino acids 1020-1091 (encoded by exon 12).

Expression

GLI proteins function as direct effectors of sonic hedgehog-signaling during embryogenesis. GLI1 (also GLI2 and GLI3) are therefore likely to be involved in the tissue-specific proliferation of the central nervous system, the zones of polarizing activity in the developing limb, and of the gut. In the adult human, GLI1 expression has been demonstrated in the testes, myometrium and Fallopian tubes.

Localisation

Nuclear. Might be fluctuating between the cytoplasm and the nucleus.

Function

DNA-binding transcription factor

Mutations

Germinal

An abnormal activity of GLI, caused by mutations affecting upstream components of the sonic hedgehog-signaling pathway (sonic hedgehog, patched or smoothened) are associated with developmental disorders.

Somatic

Various tumors of mesenchymal and lymphocytic origin.

Implicated in

Note

Rearrangement and fusion of the GLI1 gene.

Disease

Pericytoma with t(7;12)

Prognosis

Benign or low-malignant

Cytogenetics

t(7;12)(p22;q13)

Hybrid gene

ACTB-GLI1 fusion gene. The breakpoints reported so far have been located to introns 1, 2 or 3 within the ACTB gene, and to introns 5 or 6 or to exon 7 within the GLI1 gene. Reciprocal GLI1-ACTB gene fusions have also been detected. The breakpoints have been located to introns 5 or 7 within the GLI1 gene, and to intron 3 of the ACTB gene.

Representative G-banded partial karyotype of the t(7;12)(p22;q13).

Fusion protein

The ACTB-GLI1 fusion protein contains the N-terminal of ACTB and the C-terminal of GLI1, including the DNA-binding zinc finger motifs (encoded by exons 7-10) and transactivating motifs (exon 12).

Oncogenesis

It is suggested that the strong ACTB promoter causes an overexpression of GLI1 sequences important for transcriptional activation of downstream target genes, akin to the oncogenic mechanisms of the COL1A1-PDGFB fusion gene detected in dermatofibrosarcoma protuberans.

Note

Amplification of the GLI1 gene

Disease

Glioma, B-cell lymphoma, sarcoma

Prognosis

Depends on tumor type

Oncogenesis

Overexpression of GLI1 sequences. Might be of prognostic importance.

Bibliography

Pubmed ID	Last Year	Title	Authors

Other Information

Locus ID:

NCBI: 2735
MIM: 165220
HGNC: 4317
Ensembl: ENSG00000111087

Variants:

dbSNP: 2735
ClinVar: 2735
TCGA: ENSG00000111087
COSMIC: GLI1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000111087	ENST00000228682	P08151
ENSG00000111087	ENST00000528432	E9PQQ1
ENSG00000111087	ENST00000528467	P08151
ENSG00000111087	ENST00000532291	E9PIB9
ENSG00000111087	ENST00000543426	P08151
ENSG00000111087	ENST00000546141	P08151

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Hedgehog signaling pathway	KEGG	ko04340
Basal cell carcinoma	KEGG	ko05217
Hedgehog signaling pathway	KEGG	hsa04340
Pathways in cancer	KEGG	hsa05200
Basal cell carcinoma	KEGG	hsa05217
cAMP signaling pathway	KEGG	hsa04024
cAMP signaling pathway	KEGG	ko04024
Hedgehog signaling	KEGG	hsa_M00678
Hedgehog signaling	KEGG	M00678
Signal Transduction	REACTOME	R-HSA-162582
Signaling by Hedgehog	REACTOME	R-HSA-5358351
Hedgehog 'off' state	REACTOME	R-HSA-5610787
Degradation of GLI1 by the proteasome	REACTOME	R-HSA-5610780
Hedgehog 'on' state	REACTOME	R-HSA-5632684
GLI proteins bind promoters of Hh responsive genes to promote transcription	REACTOME	R-HSA-5635851

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
17196391	2007	HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.	375
17628016	2007	Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma.	222
17392427	2007	Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways.	213
20049737	2009	Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion.	182
15314219	2004	Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.	172
17638910	2007	Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo.	158
20581802	2010	NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1 and p53.	123
17115028	2006	Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination.	116
20083481	2010	Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals.	110
19214186	2009	A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers.	96

Citation

Anna Dahlén ; Fredrik Mertens ; Nils Mandahl ; Ioannis Panagopoulos

GLI1 (glioma-associated oncogene homolog 1)

Atlas Genet Cytogenet Oncol Haematol. 2005-03-01

Online version: http://atlasgeneticsoncology.org/gene/310/gene-fusions/?id=310