SIAH1 (siah E3 ubiquitin protein ligase 1)

2013-02-01 Yoshito Nagano , Shu-Ichi Matsuzawa Affiliation

Hiroshima University Graduate School of Biomedical, Health Sciences, Hiroshima 734-8551, Japan (YN), Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA (SIM)

Identity

HGNC

SIAH1

LOCATION

16q12.1

IMAGE

LEGEND

Map of chromosome 16 with region 16q12.1 highlighted as the location of the gene SIAH1.

LOCUSID

6477

ALIAS

BURHAS,SIAH1A

FUSION GENES

Show Gene Fusions

DNA/RNA

Note

The human Siah1 gene is composed of 2 exons, separated by an intron of roughly 14,5 kb.

Genomic structure and exon-intron boundaries for SIAH1. The relevant DNA sequences at exon-intron boundaries are indicated, and respective amino acid sequences are indicated below in single-letter code. The entire open reading frame of SIAH1 is in exon 2, and its initiating methionine is underlined.

Pseudogene

One pseudogene has been reported.

Proteins

Schema of Siah1 structure. Siah1 has RING domain at the N-terminus and the substrate binding domain (SBD) at the C-terminus. Some substrate proteins are recognized by this substrate binding domain directly, and receive ubiquitin-conjugation.

Expression

Siah1 mRNA is widely expressed in the human tissues. It is expressed at higher level in placenta, skeletal muscle and testis.

Localisation

Siah1 protein can be localized in both cytoplasm and nucleus.

Function

Siah1 is the mammalian homolog of Drosophia seven in absentia (SINA) protein (Carthew and Rubin, 1990). Siah1 protein plays a key role in biological processes such as the cell cycle, programmed cell death, and oncogenesis (Nemani et al., 1996). The Siah family of RING-domain proteins are components of ubiquitin ligase complexes, targeting proteins for proteasomal degradation. Numerous substrates targeted for degradation by Siah proteins have been reported; Synphilin-1 (Nagano et al., 2003), DCC (Hu et al., 1997), N-CoR (Zhang et al., 1998), BOB1/OBF1 (Boehm et al., 2001, Tiedt et al., 2001), c-Myb (Tanikawa et al., 2000), Kid (Germani et al., 2000) and CtIP (Germani et al., 2003). Siah1 expression is upregulated by p53, revealing a link between genotoxic injury and destruction of β-catenin and reduced T-cell factor/lymphoid enhancer factor (Tcf/Lef) activity (Liu et al., 2001; Jansen et al., 2009). Recent paper showed Siah1 expression facilitates ubiquitination and degradation of the tumor suppressor HIPK2 that is a key regulator of the apoptotic programme induced by DNA damage (Winter et al., 2008).
It has been shown that the nuclear translocation and accumulation of GAPDH play important roles in early events leading to cell death initiation and execution (Sirover, 1999), resulting in the various degenerative diseases. Siah1 functions as a potential carrier/shuttle proteins for the induction of GAPDH nuclear translocation because of its nuclear location signal (NLS) domain in Siah1 (Hara et al., 2005).
Siah1a knockout mice are growth-retarded, exhibit early lethality, and display spermatogenetic defects. They also exhibit high numbers of osteoclasts with low numbers of osteoblasts, resulting in severe osteopenia (Frew et al., 2004).

Homology

Human: Siah2.
Mouse: Siah1a, Siah1b, Siah2.

Mutations

Note

There is limited evidence for mutation, with only one report of a low frequency of inactivating mutations in gastric cancer (Kim et al., 2004).

Implicated in

Entity name

Breast cancer

Note

Wen et al. showed that Siah1 overexpression induced cell apoptosis by up-regulating the level of Bim through the activation of the JNK signaling pathway, and the suppression of Siah1 expression increased cell invasion via the activation of the ERK signaling pathway in breast cancer cells (Wen et al., 2010a; Wen et al., 2010b).
He et al. showed that overexpression of Siah1 enhanced radiation-induced apoptosis in breast cancer cells (He et al., 2010).
Those data suggest that Siah1 can be a novel therapeutic target for tumor cell death.

Entity name

Leukemia

Note

Krämer et al. showed that the leukemia fusion protein PML-RARα (promyelocytic leukemia-retinoic acid receptor α which causes acute promyelocytic leukemias, is degraded by ubiquitin-proteasome system and that their turnover critically depends on the E2-conjugase UbcH8 and Siah1. They also showed that HDAC inhibitor enhanced the degradation of leukemia fusion proteins via UbcH8-Siah1 axis and could be a new therapeutic strategy for leukemia (Krämer et al., 2008).

Entity name

Gastric cancer

Note

Kim et al. found two missense mutations in the SIAH1 gene in gastric cancer. The two mutants revealed that impairment of β-catenin degradation pathway, increase of cyclin D1 expression, and inhibition of apoptosis in culture cells, suggesting that mutations of Siah1 gene may play an important role in the development and progression in a subset of gastric cancer through β-catenin stabilization and apoptosis block (Kim et al., 2004).

Entity name

Hepatocellular carcinoma

Note

Matsuo et al. showed that the expression level of SIAH1 was markedly downregulated in hepatocellular carcinoma (HCC), especially in advanced stages (Matsuo et al., 2003). Okabe et al. showed that the paternally expressed gene 10 (PEG10) was an important factor in HCC progression as a substrate for Siah1 and could be a novel molecular target for treatment (Okabe et al., 2003).

Entity name

Parkinsons disease

Note

Nagano et al. showed for the first time that Siah1 ubiquitinated α-synuclein-interacting protein, Synphilin-1, leading to degradation. These proteins are located in Lewy body, the pathological hallmark of Parkinsons disease (Nagano et al., 2003). Recent papers showed that Siah1 facilitated mono- or di-ubiquitination of α-synuclein, leading to Lewy body formation (Lee et al., 2008; Rott et al., 2008). But no mutation in Siah1 has been identified in Parkinsons disease patients (Franck et al., 2006).

Bibliography

Pubmed ID	Last Year	Title	Authors
11483518	2001	Regulation of BOB.1/OBF.1 stability by SIAH.	Boehm J et al
2146028	1990	seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye.	Carthew RW et al
16752048	2006	Mutation analysis of the seven in absentia homolog 1 (SIAH1) gene in Parkinson's disease.	Franck T et al
15123657	2004	Osteopenia in Siah1a mutant mice.	Frew IJ et al
11146551	2000	SIAH-1 interacts with alpha-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis.	Germani A et al
14654780	2003	SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway.	Germani A et al
15951807	2005	S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.	Hara MR et al
20682032	2010	Siah1 proteins enhance radiosensitivity of human breast cancer cells.	He HT et al
9334332	1997	Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway.	Hu G et al
18629630	2009	Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer.	Jansen MP et al
15467739	2004	Inactivating mutations of the Siah-1 gene in gastric cancer.	Kim CJ et al
18073335	2008	Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha.	Krämer OH et al
18065497	2008	Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death.	Lee JT et al
11389840	2001	Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein.	Liu J et al
12557228	2003	SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas.	Matsuo K et al
14506261	2003	Siah-1 facilitates ubiquitination and degradation of synphilin-1.	Nagano Y et al
8799150	1996	Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression.	Nemani M et al
12810624	2003	Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1.	Okabe H et al
18070888	2008	Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells.	Rott R et al
10407139	1999	New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase.	Sirover MA et al
10747903	2000	p53 suppresses the c-Myb-induced activation of heat shock transcription factor 3.	Tanikawa J et al
11483517	2001	The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1.	Tiedt R et al
19775288	2010	SIAH1 induced apoptosis by activation of the JNK pathway and inhibited invasion by inactivation of the ERK pathway in breast cancer cells.	Wen YY et al
18536714	2008	Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR.	Winter M et al
9637679	1998	Proteasomal regulation of nuclear receptor corepressor-mediated repression.	Zhang J et al

Other Information

Locus ID:

NCBI: 6477
MIM: 602212
HGNC: 10857
Ensembl: ENSG00000196470

Variants:

dbSNP: 6477
ClinVar: 6477
TCGA: ENSG00000196470
COSMIC: SIAH1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000196470	ENST00000356721	Q8IUQ4
ENSG00000196470	ENST00000380006	Q8IUQ4
ENSG00000196470	ENST00000394725	Q8IUQ4
ENSG00000196470	ENST00000563745	H3BU09
ENSG00000196470	ENST00000568007	Q8IUQ4

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
p53 signaling pathway	KEGG	ko04115
Ubiquitin mediated proteolysis	KEGG	ko04120
Wnt signaling pathway	KEGG	ko04310
p53 signaling pathway	KEGG	hsa04115
Ubiquitin mediated proteolysis	KEGG	hsa04120
Wnt signaling pathway	KEGG	hsa04310
Metabolism of proteins	REACTOME	R-HSA-392499
Amyloid fiber formation	REACTOME	R-HSA-977225
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Class I MHC mediated antigen processing & presentation	REACTOME	R-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradation	REACTOME	R-HSA-983168
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
Netrin-1 signaling	REACTOME	R-HSA-373752

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
15951807	2005	S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.	362
12399545	2002	Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1.	73
11786535	2002	Regulation of synaptophysin degradation by mammalian homologues of seven in absentia.	68
18536714	2008	Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR.	68
18070888	2008	Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells.	62
18065497	2008	Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death.	58
12810624	2003	Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1.	41
16615911	2006	Elucidation of the substrate binding site of Siah ubiquitin ligase.	36
20181957	2010	Direct ubiquitination of beta-catenin by Siah-1 and regulation by the exchange factor TBL1.	36
16085652	2005	Structural analysis of Siah1-Siah-interacting protein interactions and insights into the assembly of an E3 ligase multiprotein complex.	35

Citation

Yoshito Nagano ; Shu-Ichi Matsuzawa

SIAH1 (siah E3 ubiquitin protein ligase 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-02-01

Online version: http://atlasgeneticsoncology.org/gene/457/siah1-(siah-e3-ubiquitin-protein-ligase-1)