E3 ubiquitin-protein ligase SIAH1; seven in absentia homolog 1; siah-1; siah-1a (SIAH1 HUMSIAH)

Function

• E3-ubiquitin ligage that mediates mediates ubiquitination & subsequent proteasomal degradation of target proteins
• triggers ubiquitin-mediated degradation of
  • proteins involved in transcription regulation (MYB, POU2AF1, PML & RBBP8)
  • cell surface receptor (DCC)
  • cytoplasmic signal transduction molecules (KLF10/TIEG1 & NUMB)
  • an antiapoptotic protein (BAG1)
  • microtubule motor protein (KIF22)
  • protein involved in synaptic vesicle function in neurons (SYP)
  • structural protein (CTNNB1)
  • SNCAIP
• involved in many cellular processes such as
  • apoptosis
  • tumor suppression
  • cell cycle
  • axon guidance
  • transcription regulation
  • spermatogenesis
  • TNF-alpha signaling
• has some overlapping function with SIAH2
• induces apoptosis in cooperation with PEG3
• upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating translocation of GAPDH to the nucleus
• GAPDH acts as a stabilizer of SIAH1, facilitating degradation of nuclear proteins
• turnover in the absence of stabilization is rapid
• overexpression inhibits cell proliferation, promotes apoptosis & suppresses tumor formation
• inhibited by interaction with SNCAIP (isoform 2, but not isoform 1)
• may be inhibited by interaction with PEG10
• protein modification; protein ubiquitination
• homodimer
• interacts with group 1 glutamate receptors GRM1 & GRM5
• interacts with DAB1, which may inhibit its activity
• interacts with UBE2E2. interacts with PEG3
• interacts with GAPDH; leading to stabilize SIAH1 (putative)
• component of some large E3 complex composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC & TBL1X
• interacts with UBE2I
• interacts with alpha- tubulin
• interacts with PEG10, which may inhibit its activity
• interacts with KHDRBS3
• interacts with SNCAIP

Structure

• the RING-type Zn+2 finger domain is essential for ubiquitin ligase activity
• the SBD domain (substrate-binding domain) mediates homodimerization & interaction with substrates
• related to the TRAF family (putative)
• belongs to the SINA (seven in absentia) family
• contains 1 RING-type Zn+2 finger
• contains 1 SIAH-type Zn+2 finger

Compartment

• cytoplasm, nucleus
• predominantly cytoplasmic, partially nuclear

Alternative splicing

named isoforms=3

Expression

• widely expressed at low level
• down-regulated in advanced hepatocellular carcinomas
• can be induced by p53 & genotoxic stress

More general terms

• E3 ubiquitin ligase
• zinc finger protein

Additional terms

• glyceraldehyde-3-phosphate dehydrogenase (GAPDH, GAPD, CDABP0047, OK/SW-cl12)
• paternally expressed gene 3 protein (PEG3, KIAA0287)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=6477
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:6477
• OMIM: https://mirror.omim.org/entry/602212
• UniProt: http://www.uniprot.org/uniprot/Q8IUQ4.html