Disease relevance of SIP1

• Mutations in ZFHX1B, encoding Smad-interacting protein 1 (SIP1), have been recently reported to cause a form of Hirschsprung disease (HSCR) [1].
• In muscle specimens from patients with spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), the expression of SIP1-alpha was dramatically decreased compared to that observed in the normal tissues [2].
• SIP1 is also expressed in some breast cancer cell lines and was detected in intestinal gastric carcinomas, where its expression is inversely correlated with that of E-cadherin [3].
• An essential SMN interacting protein (SIP1) is not involved in the phenotypic variability of spinal muscular atrophy (SMA) [4].
• SIP1 therefore appears to be a promoter of invasion in malignant epithelial tumors [5].

Psychiatry related information on SIP1

• Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with "syndromic Hirschsprung disease" with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al [6].

High impact information on SIP1

• Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease [7].
• SIP1 seems to have crucial roles in normal embryonic neural and neural crest development [7].
• We found that SMN is tightly associated with a novel protein, SIP1, and together they form a specific complex with several spliceosomal snRNP proteins [8].
• Thus, the SMN-SIP1 complex is directly involved in the biogenesis of spliceosomal snRNPs [9].
• Here we show that the SMN-SIP1 complex is associated with spliceosomal snRNAs U1 and U5 in the cytoplasm of Xenopus oocytes [9].

Chemical compound and disease context of SIP1

• Expression of Snail, SIP1, and Twist was analyzed in 48 gastric carcinomas by real-time quantitative RT-PCR in paraffin-embedded and formalin-fixed tissues [10].

Biological context of SIP1

• Survival motor neuron (SMN) interacting protein 1 (SIP1) interacts with SMN protein and plays a crucial role in the biogenesis of spliceosomes [2].
• Next, we determined the exon-intron structure of the SIP1 gene which encompasses 10 exons and identified five transcription isoforms [4].
• These findings suggest that an aberrant alternative splicing event in SIP1 occurs tissues derived from patients with the motor neuron diseases, and contributes to the pathological process of SMA and ALS [2].
• SIP1/ZEB2 is a member of the deltaEF-1 family of two-handed zinc finger nuclear factors [3].
• Here, we show that expression of SIP1 in human epithelial cells results in a clear morphological change from an epithelial to a mesenchymal phenotype [3].

Anatomical context of SIP1

• Increased expression level of the splicing variant of SIP1 in motor neuron diseases [2].
• Besides E-cadherin, other genes coding for crucial proteins of tight junctions, desmosomes and gap junctions were found to be transcriptionally regulated by the transcriptional repressor SIP1 [3].
• In the vast majority of cultured cells and in all primary neurons analyzed, SMN and SIP1 colocalize precisely with snRNPs in the Cajal body [11].
• It was previously reported that in HeLa cells, SMN and SIP1 form discrete foci located next to Cajal (coiled) bodies, the so-called "gemini of coiled bodies" or "gems." An intriguing feature of gems is that they do not appear to contain snRNPs [11].
• The N terminus of SMN was required for the recruitment of Gemin2 into cytoplasmic granules and enhanced Gemin2 stability [12].

Associations of SIP1 with chemical compounds

• Finally, treatment of cells with leptomycin B (a drug that blocks export of U snRNAs to the cytoplasm and consequently import of new snRNPs into the nucleus) is shown to deplete snRNPs (but not SMN or SIP1) from the Cajal body [11].

Physical interactions of SIP1

• The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis [9].

Other interactions of SIP1

• Recently, two novel proteins involved in biogenesis of small nuclear ribonucleoproteins (snRNPs) were identified, the Spinal muscular atrophy disease gene product (SMN) and its associated protein SIP1 [11].
• In both compartments SMN is part of a large complex that contains several proteins including Gemin2 (formerly SIP1) and the DEAD box protein Gemin3 [13].
• SMN is part of a multi-protein complex that includes Gemin2, Gemin3, and Gemin4 [14].
• SMN associates with several proteins (Gemin2 to Gemin6) to form a large complex which is found both in the cytoplasm and in the nucleus [15].
• Identification of a novel human immunodeficiency virus type 1 integrase interactor, Gemin2, that facilitates efficient viral cDNA synthesis in vivo [16].

Analytical, diagnostic and therapeutic context of SIP1

• The presence of SMN and SIP1 in Cajal bodies is confirmed by immunoelectron microscopy and by microinjection of antibodies that interfere with the integrity of the structure [11].
• ELISA detected IgG specific to Sip1 C-ter in sera from 11/56 (20%) patients with Behçet's disease, IgM in 23/56 (41%) and IgA in 9/54 (17%) [17].

References