CASZ1 (castor zinc finger 1)

2013-01-01   Zhihui Liu , Nancy Ding , Carol J Thiele 

Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, USA

Identity

HGNC
LOCATION
1p36.22
LOCUSID
ALIAS
CAS11,CST,SRG,ZNF693,dJ734G22.1
FUSION GENES

DNA/RNA

Atlas Image
Location of DNA of CASZ1 and two forms of the gene due to alternative splicing.

Description

DNA of CASZ1a contains 160072 bp composed of 21 exons with 11 zinc fingers, alternative splicing at exon 16 of CASZ1a can result in CASZ1b (16 exons with 5 zinc fingers) (Liu et al., 2006).

Transcription

CASZ1 mRNA transcribed in centromeric to telomeric orientation. The CASZ1a cDNA sequence spans 7964 bp, with a 5 UTR of 346 bp, an open reading frame of 5280 bp, and a 3 UTR of 2339 bp; the CASZ1b cDNA sequence spans 4438 bp, with a 5 UTR of 346 bp, an open reading frame of 3501 bp, and a 3 UTR of 592 bp (Liu et al., 2006; with updated information from NCBI database).

Proteins

Atlas Image
Functional domains of CASZ1.

Description

The 5 of CASZ1 contains 2 nuclear localization signals, which tag proteins for import into the cell nucleus, followed by 5 zinc fingers of C2H2 type (Cys2His2). C2H2 zinc fingers are thought to have DNA binding and protein-protein mediation roles. For CASZ1a, six other zinc fingers (ZF) are present along with a third nuclear localization signal between ZF8 and ZF9. CASZ1b totals 1166 amino acids and CASZ1a totals 1794 amino acids (Liu et al., 2006; Virden et al., 2012).

Expression

Increased expression when cells of neural and mesenchymal origin are induced to differentiation in vitro. CASZ1 is highly expressed in eye, heart, lung, skeletal muscle, pancreas, testis, small intestine and stomach (Liu et al., 2006; Liu et al., 2011a). CASZ1 is dynamically expressed in the development heart and during neurogenesis (Vacalla and Theil, 2002).

Localisation

Nucleus, cytoplasm.

Function

CASZ1 is a crucial zinc finger transcription factor that controls the differentiation of neural (Cui and Doe, 1992) and cardiac muscle cells (Christine and Conlon, 2008), eye development (Vacalla and Theil, 2002) and has tumor suppressor properties (Liu et al., 2011b). There is monoallelic loss of CASZ1 in neuroblastoma (NB) tumors through loss of heterozygosity (LOH) and epigenetic silencing (Wang et al., 2012). Restoration of CASZ1 in NB cells induces cell differentiation, inhibits cell migration and suppresses NB growth (Liu et al., 2011a; Liu et al., 2011b). Structural and functional studies show that either deletion of the N-terminus or mutation in any of the first four zinc fingers of CASZ1b results in a drastic loss in transcriptional activity, which also leads to a decreased tumor suppression activity (Virden et al., 2012). Additionally, single nucleotide polymorphisms in this gene are associated with blood pressure variations in East Asian populations (Takeuchi et al., 2010).

Homology

Unknown.

Mutations

Note

Unknown.

Implicated in

Entity name
Neuroblastoma
Note
Neuroblastomas (NB) are pediatric cancers arising from cells of the sympathoadrenal lineage of neural crest cells (Brodeur, 2003; Maris, 2010). CASZ1 maps to 1p36.22, part of the most commonly deleted regions of chromosome 1p that occur in 35% of NB cases (Brodeur, 2003). A recent study in 184 primary NB showed that 1p36.3 is the shortest region of overlap for loss of heterozygosity (LOH) (White et al., 2005), although 98% of these 1p36.3 LOH NB tumors also have lost the region encompassing CASZ1 (Liu et al., 2011b). Additionally, CASZ1 is epigenetically silenced in NB by EZH2, a methyltransferase (Wang et al., 2012). HDAC inhibitor treatment of NB cells increases CASZ1 expression (Carén et al., 2007; Fransson et al., 2007). Consistent with CASZ1 being epigenetically regulated, a bivalent mark was found in CASZ1 promoter region in ES cells (Bernstein et al., 2006). CASZ1 is upregulated when NB cells are induced to differentiate by retinoic acid, and restoration of CASZ1 in NB cells up-regulates differentiation genes such as NGFR and TrkA, and suppresses tumor growth (Liu et al., 2011a; Liu et al., 2011b). In NB patients, low CASZ1 expression in NB tumors is associated with poor prognosis and an undifferentiated histology, which suggests loss of CASZ1 may contribute to NB tumorigenesis.
Entity name
Cervical carcinoma
Note
Human papillomavirus (HPV) genome integration into host chromatin enables expression of oncogenes E6 and E7 leading to cervical carcinogenesis. HPV integration may affect transcriptionally active sites. In one reported case of cervical cancer, HPV was found to functionally delete CASZ1 (Schmitz et al., 2012).
Entity name
Blood hypertension
Note
Hypertension, increases in blood pressure, can lead to cardiovascular disease including stroke and ischemic heart disease. CASZ1 has been found to be one of seven loci associated with hypertension in East Asian populations (Takeuchi et al., 2010). CASZ1 could be linked to heart malfunction through inflammatory responses. CASZ1 had been found to have associations in European ancestry but Japanese loci effect size was significantly larger (Takeuchi et al., 2010).

Bibliography

Pubmed IDLast YearTitleAuthors
166308192006A bivalent chromatin structure marks key developmental genes in embryonic stem cells.Bernstein BE et al
126126552003Neuroblastoma: biological insights into a clinical enigma.Brodeur GM et al
179405112007Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours.Carén H et al
184107362008Vertebrate CASTOR is required for differentiation of cardiac precursor cells at the ventral midline.Christine KS et al
13393401992ming is expressed in neuroblast sublineages and regulates gene expression in the Drosophila central nervous system.Cui X et al
170440482007Neuroblastoma tumors with favorable and unfavorable outcomes: Significant differences in mRNA expression of genes mapped at 1p36.2.Fransson S et al
214909192011CASZ1b, the short isoform of CASZ1 gene, coexpresses with CASZ1a during neurogenesis and suppresses neuroblastoma cell growth.Liu Z et al
212529122011CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression.Liu Z et al
205583712010Recent advances in neuroblastoma.Maris JM et al
222623982012Loss of gene function as a consequence of human papillomavirus DNA integration.Schmitz M et al
204791552010Blood pressure and hypertension are associated with 7 loci in the Japanese population.Takeuchi F et al
123511992002Cst, a novel mouse gene related to Drosophila Castor, exhibits dynamic expression patterns during neurogenesis and heart development.Vacalla CM et al
223314712012Characterization of critical domains within the tumor suppressor CASZ1 required for transcriptional regulation and growth suppression.Virden RA et al
220680362012EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR.Wang C et al
158299792005Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma.White PS et al

Other Information

Locus ID:

NCBI: 54897
MIM: 609895
HGNC: 26002
Ensembl: ENSG00000130940

Variants:

dbSNP: 54897
ClinVar: 54897
TCGA: ENSG00000130940
COSMIC: CASZ1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000130940ENST00000344008Q86V15
ENSG00000130940ENST00000377022Q86V15
ENSG00000130940ENST00000447850K7EQC6

Expression (GTEx)

0
10
20
30
40
50
60
70

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
194304792009Genome-wide association study of blood pressure and hypertension.542
204791552010Blood pressure and hypertension are associated with 7 loci in the Japanese population.63
220680362012EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR.61
212529122011CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression.39
166316142006Molecular cloning and characterization of human Castor, a novel human gene upregulated during cell differentiation.28
222623982012Loss of gene function as a consequence of human papillomavirus DNA integration.25
214909192011CASZ1b, the short isoform of CASZ1 gene, coexpresses with CASZ1a during neurogenesis and suppresses neuroblastoma cell growth.15
223314712012Characterization of critical domains within the tumor suppressor CASZ1 required for transcriptional regulation and growth suppression.11
238924352013CASZ1 inhibits cell cycle progression in neuroblastoma by restoring pRb activity.11
262969752015Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription.7

Citation

Zhihui Liu ; Nancy Ding ; Carol J Thiele

CASZ1 (castor zinc finger 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-01-01

Online version: http://atlasgeneticsoncology.org/gene/45989/casz1