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SKI-INTERACTING PROTEIN; SKIIP

SKI-INTERACTING PROTEIN; SKIIP

Alternative titles; symbolsSKIPBX42, DROSOPHILA, HOMOLOG OFSNW1HGNC Approved Gene Symbol: SNW1Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:...

Alternative titles; symbols

  • SKIP
  • BX42, DROSOPHILA, HOMOLOG OF
  • SNW1

HGNC Approved Gene Symbol: SNW1

Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:77,717,598-77,761,155 (from NCBI)

▼ Description
SKIIP exhibits properties of a nuclear receptor coactivator in that it interacts with nuclear receptors and enhances ligand-activated transcription. It also interacts with spliceosome components, suggesting that it may function as a coupling factor that links nuclear receptor-dependent transcription to RNA processing (summary by Zhang et al. (2003)).

▼ Cloning and Expression
The Drosophila Bx42 nuclear protein binds to a specific subset of puffs on polytene chromosomes in response to the steroid hormone ecdysone, and is thought to play a role in the regulation of chromatin. Folk et al. (1996) cloned a Dictyostelium gene, snwA, that contains an SH2 motif and has homology to Bx42. By searching an EST database for snwA homologs, Folk et al. (1996) identified a partial human cDNA encoding a protein that they designated SNW1. Using a 2-hybrid screen to identify proteins that interact with the SKI (164780) retroviral oncogene, Dahl et al. (1998) independently isolated human SNW1 cDNAs. They called the gene SKIP for 'SKI-interacting protein.' The predicted 536-amino acid protein shares nearly 60% amino acid identity with Bx42.

Using Northern blot analysis, Baudino et al. (1998) found that human SKIP was expressed widely as a 2.2-kb mRNA.

Zhang et al. (2003) identified a nuclear localization signal at the C terminus of SKIP. Endogenous SKIP showed strict nuclear localization in COS-7, HeLa, SaOS-2, and rat osteosarcoma cells, and it distributed in a fine punctate subnuclear pattern in these cells.

▼ Gene Function
Dahl et al. (1998) found that SKIP associated with SKI in both in vitro and in vivo assays. By analysis of mutant SKI proteins, they determined that SKIP interacts with a highly conserved region of SKI that is required for transforming activity. Cell fractionation and immunofluorescence studies revealed that SKIP, like SKI, is found within the nucleus. However, the SKI and SKIP localization patterns are not identical, suggesting that the 2 proteins are not always bound to each other and that their association may be regulated by other factors.

Using a yeast 2-hybrid screen, Baudino et al. (1998) identified SKIP, or NCoA-62 (for 'nuclear receptor coactivator, 62-kD'), as a protein that forms a direct protein-protein contact with the ligand-binding domain of the vitamin D receptor (VDR; 601769) and interacts with retinoid receptors. SKIP expression enhanced vitamin D-, retinoic acid-, estrogen-, and glucocorticoid-mediated gene expression. These authors suggested that SKIP is one of a set of transcriptional coactivator proteins that function to facilitate vitamin D- and other nuclear receptor-mediated transcriptional pathways.

Using various extraction procedures, Zhang et al. (2003) showed that endogenous SKIP was tightly associated with the nuclear matrix in rat and human osteosarcoma cells. Chromatin immunoprecipitation assays showed that Skip colocalized with Vdr on vitamin D-responsive elements (VDREs). Crosslinking and immunoprecipitation experiments showed that endogenous Vdr, Src1 (NCOA1; 602691), and Skip associated with VDREs in the rat 24-hydroxylase (CYP24A1; 126065) promoter following treatment with activated vitamin D (1,25-(OH)2D3). Protein pull-down assays, followed by SDS-PAGE and mass spectrometry, revealed that human SKIP interacted with several components of the spliceosome in HeLa cell nuclear extracts. Expression of a dominant-negative SKIP in COS-7 cells interfered with proper splicing of transcripts derived from a growth hormone (GH1; 139250) minigene in response to 1,25-(OH)2D3 treatment. Zhang et al. (2003) concluded that SKIP couples VDR-mediated transcription to RNA splicing.

Oculopharyngeal muscular dystrophy (OPMD; 164300) is caused by short expansions of the GCG trinucleotide repeat encoding the polyalanine tract of the poly(A)-binding protein 2 (PABP2; 602279). Kim et al. (2001) established stable mouse skeletal muscle C2 cell lines expressing human PABP2. The cells showed morphologically enhanced myotube formation accompanied by an increased transcription of myogenic factors MyoD (159970) and myogenin (159980). Using a yeast 2-hybrid system, SKIP was shown to bind to PABP2. Immunofluorescence studies showed that PABP2 colocalized with SKIP in nuclear speckles. Reporter assays showed that PABP2 cooperated with SKIP to synergistically activate E-box-mediated transcription through MyoD. Moreover, both PABP2 and SKIP were directly associated with MyoD to form a single complex. The authors suggested that PABP2 and SKIP directly control the expression of muscle-specific genes at the transcriptional level.

Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was SKIIP. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown.

By yeast 2-hybrid analysis of a fetal brain cDNA library, Scott and Plon (2005) found that the C-terminal domain of the transcriptional repressor FOXN3 (602628) interacted with SKIIP. Coimmunoprecipitation analysis of epitope-tagged proteins confirmed the interaction in HeLa cells. Domain analysis revealed that the extreme C terminus of SKIIP interacted with the C-terminal domain of FOXN3.

Tags: 14q24.3