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FLASH GENE

Symbol

SIAH1

contributors: mct - updated : 18-01-2016

HGNC name	seven in absentia homolog 1 (Drosophila)
HGNC id	10857

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	16q12.1      Physical location : 48.394.445 - 48.419.229
Synonym name	sonic hedgehog (Drosophila) homolog
	E3 ubiquitin-protein ligase SIAH1
Synonym symbol(s)	Siah-1, HUMSIAH, Siah-1a, FLJ08065
EC.number	6.3.2.-

DNA

TYPE	functioning gene
STRUCTURE	87.91 kb     2 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Binding site
text structure	one Sp1 site responsible of the basal promoter activity

MAPPING

cloned

Y

linked

N

status

provisional

Physical map

RNA

TRANSCRIPTS	type	messenger

text	may be three transcripts (Mips)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003031 2 splicing 2003 NP_003022 31.1 282 - 2007 17420721 also called variant 1, or SIAH1S interact with SIAH1 to form heterodimer or with itself to form homodimer displays a promotion effect on cells tumorigenicity variant 3 - - 33200 isoform 3 - 299 - Mips variant 4 - - 36900 isoform 4 - 344 - Mips NM_001006610 2 - 2393 NP_001006611 - 313 - 2007 17420721 also called variant 2, or SIAH1L upregulated by TP53 induced in response to TP53 and plays an important role in the regulation of beta-catenin activity in tumor cells

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     highly Endocrine thyroid       highly Reproductive female system ovary         male system prostate       Urinary kidney         Visual eye anterior segment iris   highly   eye retina     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow

cells

System Cell Pubmed Species Stage Rna symbol Nervous Purkinje cell

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text

eye

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal RING zinc finger motif confering its ability to work as an E3 ubiquitin-ligase and required for the transactivation
	conserved ALF domain
	C-terminal domain implicated in the binding of different substrate proteins (the presynaptic protein synaptophysin), and may regulate substrate binding ability

HOMOLOGY

interspecies

homolog to Drosophila seven in absentia (sina) 1

Homologene

FAMILY

E3 ligase family

CATEGORY

regulatory , tumor suppressor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm,nuclear bodies
text	co-localized with PHC2 in nuclei
	HIPK2 colocalizes with its ubiquitin ligase SIAH1 at nuclear bodies, suggesting that these nuclear domains are the site of HIPK2 ubiquitination

basic FUNCTION	involved in external sensory organ development
	requiring for specification of r7 photoreceptor cell fate in the Drosophila eye
	involved in a variety of cellular processes such as apoptosis and tumor suppression
	contributing to death of neurons and other cell types by activating the JNK pathway, activity that requires its E3 ligase activity
	E3 ligase involved in ubiquitination and proteasome-mediated degradation of specific proteins
	able to facilitate the ubiquitination and degradation of PHC2 via ubiquitin–proteasome pathway
	plays a critical role in the process of GAPDH nuclear translocation (Chepchumba 2010)
	SIAH1 ubiquitination pathway provides a fresh avenue for developing strategies to control disease-related transcription
	SIAH1 and SIAH2 isoforms share high sequence similarity but possess contrary roles in cancer, with SIAH1 more often acting as a tumor suppressor
	SIAH1 is the key factor that contributes to hypoxia and high glucose mediated synaptophysin degradation
	E3 ubiquitin ligases SIAH1 and SIAH2 are able to dictate the growth, development, and chemo-/radiosensitivity of breast and prostate cancer cells

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

SIAH1-PARD3 signaling pathway that controls adhesion-dependent exit of neuronal progenitors or immature neurons from a germinal zone niche

a component

INTERACTION

DNA

RNA

small molecule

protein	DCC
	NCOR
	POU2AF1 and leading to their destabilization and degradation through the ubiquitin-proteosome pathway
	interacting with SNCAIP (ubiquitylation of SNCAIP)
	interacting with RBBP8, leading to RBBP8 degradation by the ubiquitin-proteasome pathway
	interacts with the scaffold protein SH3RF1 to promote JNK activation and apoptosis
	interact with the JmjC domain of HIF1AN through its substrate-binding domain and to specifically ubiquitinate HIF1A via its RING finger domain
	interacting with SNCA and binding the brain-enriched E2 ubiquitin-conjugating enzyme UBE2E2 (facilitates mono- and di-ubiquitination of SNCA, promoting aggregation and apoptotic cell death, and playing a critical role in Lewy body formation and Parkinson pathogenesis)
	could interact with TRB3 (SIAH1 targeted TRB3 for proteasome-dependent degradation)
	interacted with, and ubiquitinated HIF1AN
	interacting with GAPDH (binds SIAH1, forming a complex subsequently promoting translocation of GAPDH from the cytosol to the nucleus and NLS on SIAH1 facilitates the nuclear movement of the complex) (Chepchumba 2010)
	SIAH1 induces the degradation of Kid (KIF22), a chromokinesin protein implicated in the normal progression of mitosis and meiosis, by the ubiquitin proteasome pathway
	PRPS1 interacts with the E3 ligase SIAH1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP
	EEF1D is a SIAH1-interacting protein, and EFF1D functions as a novel negative regulator of SIAH1
	RING domain protein SIAH1, but not the homologous SIAH2, is the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation
	GAPDH–SIAH1 interaction is augmented by S-nitrosylation of GAPDH
	NPM1 physiologically bound to both SIAH1 and GAPDH, disrupting the SIAH1–GAPDH complex in the nucleus in response to nitrosative stress
	interaction of TNK2 with SIAH1 and the induction of proteasomal degradation of TNK2 by SIAH1 are independent of ACK1 kinase activity
	SIAH1 and SIAH2 are binding partners of USP19, interaction mediated by a SIAH-consensus binding motif and promoting USP19 ubiquitylation and proteasome-dependent degradation
	PIN1 regulates SIAH1–mediated HIPK2 ubiquitination and degradation
	a COPS5/CTNNB1/SIAH1 interaction network that might control CTNNB1 degradation in colorectal cancer cells
	MAP3K5 a representative stress kinase, interacts with both GAPDH and SIAH1 and is likely able to phosphorylate Siah1 at specific amino acid residues
	CDK2 phosphorylation regulates the protein stability of KLF10 by interfering with binding of the E3 ligase SIAH1
	ABL1 protected HIPK2 from degradation mediated by the ubiquitin E3 ligase SIAH1
	dissociation of the GAPDH/SIAH1 pro-apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of Diabetic retinopathy (DR)

cell & other

REGULATION

induced by

TP53 and WAF1

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in hepatocellular carcinoma in progression

Susceptibility

to Parkinson disease (role in the formation of cellular inclusion and Lewy bodies)

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer reproductive breast it may be a good molecular therapeutic target to increase the expression level of SIAH1 through promoting cell apoptosis and inhibiting cell invasion in human breast cancer cancer     viable drug target for antitumor therapies

ANIMAL & CELL MODELS