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XIAP-ASSOCIATED FACTOR 1; XAF1

XIAP-ASSOCIATED FACTOR 1; XAF1

HGNC Approved Gene Symbol: XAF1Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:6,755,407-6,775,646 (from NCBI)▼ DescriptionX-linked inhibitor ...

HGNC Approved Gene Symbol: XAF1

Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:6,755,407-6,775,646 (from NCBI)

▼ Description
X-linked inhibitor of apoptosis (XIAP; 300079) is a potent member of the IAP family. All members of this family possess baculoviral IAP (BIR) repeats, cysteine-rich domains of approximately 80 amino acids that bind and inhibit caspases (e.g., CASP3; 600636). XIAP has 3 BIR domains and a C-terminal RING zinc finger that possesses E3 ubiquitin ligase (see 601623) activity. XAF1 antagonizes the anticaspase activity of XIAP and may be important in mediating apoptosis resistance in cancer cells (Liston et al., 2001).

▼ Cloning and Expression
Using a yeast 2-hybrid screen of a placenta cDNA library with XIAP as the bait, Liston et al. (2001) isolated a cDNA encoding XAF1. Sequence analysis predicted that the 301-amino acid protein has 7 potential zinc fingers. GST pull-down and immunoprecipitation analyses confirmed the interaction between XAF1 and XIAP. Fluorescence microscopy demonstrated nuclear expression of XAF1, in contrast to the cytoplasmic expression of XIAP. Coexpression of XAF1 with XIAP showed a redistribution of XIAP to the nucleus. Functional analysis indicated that XAF1 reverses the XIAP-mediated inhibition of CASP3 and its protection against apoptosis. Northern blot analysis detected wide expression of 3.9-, 4.5-, 6.0-, and 7.0-kb XAF1 transcripts, with highest levels in heart and ovary and lowest levels in brain and testis. Many cancer cell lines showed weak or no expression of XAF1. In those that did express XAF1, the 3.9-kb transcript predominated. By real-time quantitative PCR, Fong et al. (2000) confirmed these findings in multiple cancer cell lines and noted that XIAP expression is high in cancer cell lines with little or no XAF1 expression. Western blot analysis by Liston et al. (2001) showed expression of a 34-kD XAF1 protein in cell lines with relatively high levels of XAF1 mRNA. Antisense experiments determined that loss of XAF1 expression enhances resistance to apoptosis. Fong et al. (2000) suggested that alteration in XAF1 and XIAP RNA expression levels may lead to increased apoptotic resistance and proliferation due to unregulated XIAP function in cancer cells.

▼ Gene Function
Bai et al. (2008) investigated the effects of IFNG (147570) on vascular smooth muscle cells (VSMCs) through interactions involving STAT proteins. They found that IFNG stimulation phosphorylated both STAT1 (600555) and STAT3 (102582) in human VSMCs, but not in mouse VSMCs or human endothelial cells. Activation by IFNG induced STAT3 translocation to the nucleus. Microarray analysis identified signaling candidates that were inducible by IFNG and dependent on STAT3, and RT-PCR and immunoblot analyses verified roles for XAF1 and NOXA (PMAIP1; 604959). STAT3 activation sensitized VSMCs to apoptosis triggered by both death receptor- and mitochondria-mediated pathways. Knockdown of XAF1 and NOXA expression inhibited priming of VSMCs to apoptotic stimuli by IFNG. Immunodeficient mice with human coronary artery grafts were susceptible to the proapoptotic effects of XAF1 and NOXA induced by IFNG. Bai et al. (2008) concluded that STAT1-independent signaling by IFNG via STAT3 promotes death of VSMCs.

Zhu et al. (2019) found that knockdown of Sarm1 (607732) in mouse CAD5 neuronal cells significantly upregulated expression of Xaf1. RNA sequencing analysis demonstrated that Sarm1 deficiency selectively upregulated expression of Xaf1, which in turn enhanced neuronal apoptosis in prion-infected Sarm1 -/- mice.

▼ Gene Structure
By genomic sequence analysis, Fong et al. (2000) determined that the XAF1 gene contains 7 exons spanning 18 kb. Southern blot analysis suggested that XAF1 is a single-copy gene (Liston et al., 2001).

▼ Mapping
By FISH, Fong et al. (2000) mapped the XAF1 gene to chromosome 17p13.2, just telomeric to the p53 gene (191170).

Tags: 17p13.1