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Last update 08 May 2025

XAF1

Last update 08 May 2025

Basic Info

Synonyms

BIRC4-binding protein, BIRC4BP, HSXIAPAF1

+ [4]

Introduction

Seems to function as a negative regulator of members of the IAP (inhibitor of apoptosis protein) family. Inhibits anti-caspase activity of BIRC4. Induces cleavage and inactivation of BIRC4 independent of caspase activation. Mediates TNF-alpha-induced apoptosis and is involved in apoptosis in trophoblast cells. May inhibit BIRC4 indirectly by activating the mitochondrial apoptosis pathway. After translocation to mitochondria, promotes translocation of BAX to mitochondria and cytochrome c release from mitochondria. Seems to promote the redistribution of BIRC4 from the cytoplasm to the nucleus, probably independent of BIRC4 inactivation which seems to occur in the cytoplasm. The BIRC4-XAF1 complex mediates down-regulation of BIRC5/survivin; the process requires the E3 ligase activity of BIRC4. Seems to be involved in cellular sensitivity to the proapoptotic actions of TRAIL. May be a tumor suppressor by mediating apoptosis resistance of cancer cells.

Drugs associated with XAF1

CN118217316

Patent Mining

Target

XAF1

Mechanism-

Active Org.

Suzhou Institute of Systems Medicine

Originator Org.

Suzhou Institute of Systems Medicine

Active Indication

Mouth and Tooth Diseases [+2]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ZD55-XAF1

Target

XAF1

Mechanism

XAF1 modulators

Active Org.-

Originator Org.

Shanghai Institutes for Biological Sciences CAS

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with XAF1

100 Translational Medicine associated with XAF1

0 Patents (Medical) associated with XAF1

265

Literatures (Medical) associated with XAF1

01 Feb 2025·Biochemical Genetics

Screening of Genes Associated with Immune Infiltration of Discoid Lupus Erythematosus Based on Weighted Gene Co-expression Network Analysis

Article

Author: Gu, Xuefeng ; Shu, Yongyong ; Shi, Shuo ; Han, Yuru ; Lu, Changlian ; Liu, Shuang

Discoid lupus erythematosus (DLE) is a disorder of the immune system commonly seen in women of childbearing age. The pathophysiology and aetiology are still poorly understood, and no cure is presently available. Therefore, there is an urgent need to explore the underlying molecular mechanisms, as well as search for new therapeutic targets. Gene expression data from skin biopsies samples of DLE patients and healthy controls were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between DLE and healthy control samples were identified by differential expression analysis. Samples were analysed using CIBERSORT to examine the proportion of immune infiltration. Weighted gene co-expression network analysis was used to screen for the module most relevant to immune infiltration. Candidate genes were uploaded to the TRRUST database to obtain the potential transcription factors regulating these genes. Protein-protein interaction (PPI) analysis was performed to obtain the hub genes most associated with immune infiltration among the candidate genes. A total of 273 DEGs were identified between the DLE and healthy control samples. The results of immunoinfiltration analysis showed that the abundances of resting memory CD4 T cells, activated memory CD4 T cells and M1 macrophages were significantly higher, while those of resting infiltration of plasma cells, regulatory T cells and dendritic cells were lower in DLE samples than in healthy control samples. Correlation analysis showed that ISG15, TRIM22, XAF1, IFIT2, OAS2, OAS3, OAS1, IFI44, IFI6, BST2, IFIT1 and MX2 were negatively correlated with the abundances of plasma cells, T-cell regulatory cells and resting dendritic cells and positively correlated with activated memory CD4 T cells and M1 macrophages. Our study shows that these hub genes may regulate DLE via immune-related pathways mediated by the infiltration of these immune cells.

01 Jan 2025·Neoplasia

XAF1 is secreted from stressed tumor cells to activate T cell-mediated tumor surveillance via Lck-ERK signaling

Article

Author: Ahn, Jieun ; Yoon, Ji-Hye ; Jang, Seung-Hun ; Chi, Sung-Gil ; Jang, Sungchan ; Lee, Min-Goo

X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon -γ, tumor necrosis factor -α, and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon -γ injection, Xaf1⁺^/+ tumors display significantly higher regression rate and T cell infiltration compared to Xaf1^-/- tumors while Xaf1^-/- tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.

01 Jan 2025·Cell

A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor

Article

Author: Mei, Wenbin ; Tavazoie, Sohail F ; Godina, Christopher ; Faraj Tabrizi, Schayan ; Lovisa, Anthea F ; Isaksson, Karolin ; Jernström, Helena

Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival-uncovering a hereditary basis underlying breast cancer metastasis.

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XAF1

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