Ask about this productRelated genes to: ASB8 antibody
- Gene:
- ASB8 NIH gene
- Name:
- ankyrin repeat and SOCS box containing 8
- Previous symbol:
- -
- Synonyms:
- MGC5540, FLJ21255
- Chromosome:
- 12q13.11
- Locus Type:
- gene with protein product
- Date approved:
- 2001-12-05
- Date modifiied:
- 2016-01-14
Related products to: ASB8 antibody
Related articles to: ASB8 antibody
- Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1-cargo interaction. These inhibitors also induce XPO1 degradation through the Cullin-RING E3 ligase (CRL) substrate receptor ASB8. Here we present cryo-electron microscopy structures revealing ASB8 binding to a cryptic XPO1 site that is exposed upon SINE conjugation. Unlike typical molecular glue degraders that directly bridge CRLs and substrates, SINEs bind XPO1 independently of ASB8, triggering an allosteric mechanism that enables high-affinity ASB8 recruitment, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4. - Source: PubMed
Publication date: 2025/11/21
Wing Casey EFung Ho Yee JoyceKwanten BertCagatay TolgaNiesman Ashley BJacquemyn MaartenGharghabi MehdiPermentier BrechtShakya BinitaNandi RhituparnaReady Joseph MKashyap TrinayanShacham SharonLandesman YosefLapalombella RosaDaelemans DirkChook Yuh Min - This study investigated the role of estrogen receptor beta (ERβ) in the lymph node metastasis of lung adenocarcinoma (LUAD), focusing on its interaction with tumor-associated neutrophils (TANs) and its regulation of lymphangiogenesis. Clinical analysis of LUAD patient samples revealed that high ERβ expression was correlated with positive lymph node metastasis and increased lymphatic vessel density. In vitro experiments showed that ERβ promotes neutrophil chemotaxis by regulating CCL15 transcription, whereas TANs secrete VEGF-C, enhancing lymphangiogenesis. Using an orthotopic lung cancer model, we confirmed that ERβ facilitates LUAD lymph node metastasis through TAN recruitment, and inhibiting neutrophils with anti-Ly6G antibodies or CCR1 antagonists reduced this effect. Additionally, the study found that ASB8, an E3 ubiquitin ligase, degrades ERβ through K48-linked polyubiquitination. Low ASB8 expression results in increased ERβ stability and promotes LUAD metastasis. These findings suggest that ERβ, by recruiting TANs through the CCL15-CCR1 axis, plays a key role in LUAD lymph node metastasis, with ASB8 acting as a crucial regulator of ERβ stability. Targeting ERβ and ASB8 could offer new therapeutic strategies for LUAD metastasis, warranting further investigation of their clinical applications. - Source: PubMed
Publication date: 2025/07/30
Wang YangweiHe ShiwenDiao MingxinZhao RongRen JinghuaMei PeiyuanWu ShihaoFan ShengLiao Yongde - The nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes . Selinexor, a covalent XPO1 inhibitor, and other Selective Inhibitor of Nuclear Export (SINEs) restore proper nuclear localization by blocking XPO1-cargo binding . SINEs also induce XPO1 degradation via the Cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB8 . Here we elucidate the mechanism underlying the high-affinity engagement of CRL5 with SINE-conjugated XPO1. Cryogenic electron microscopy (cryoEM) structures reveal that ASB8 binds to a cryptic site on XPO1, which becomes accessible only upon SINE conjugation. While molecular glue degraders typically interact with both CRL and the substrate , SINEs bind to XPO1 without requiring interaction with ASB8 for efficient XPO1 degradation. Instead, an allosteric mechanism facilitates high affinity XPO1-ASB8 interaction, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also observed upon treatment of the endogenous itaconate derivate 4-octyl itaconate, which suggests a native mechanism that is inadvertently exploited by synthesized XPO1 inhibitors. This allosteric XPO1 degradation mechanism of SINE compounds expands the known modes of targeted protein degradation beyond the well-characterized molecular glue degraders and proteolysis targeting chimeras of CRL4. - Source: PubMed
Publication date: 2025/06/09
Wing Casey ElizabethFung Ho Yee JoyceKwanten BertCagatay TolgaNiesman Ashley BJacquemyn MaartenGharghabi MehdiPermentier BrechtShakya BinitaNandi RhituparnaReady Joseph MKashyap TrinayanShacham SharonLandesman YosefLapalombella RosaDaelemans DirkChook Yuh Min - Selinexor (KPT-330), a small-molecule inhibitor of exportin-1 (XPO1, CRM1) with potent anticancer activity, has recently been granted FDA approval for treatment of relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL), with a number of additional indications currently under clinical investigation. Since selinexor has often demonstrated synergy when used in combination with other drugs, notably bortezomib and dexamethasone, a more comprehensive approach to uncover new beneficial interactions would be of great value. Moreover, stratifying patients, personalizing therapeutics and improving clinical outcomes requires a better understanding of the genetic vulnerabilities and resistance mechanisms underlying drug response. Here, we used CRISPR-Cas9 loss-of-function chemogenetic screening to identify drug-gene interactions with selinexor in chronic myeloid leukemia, multiple myeloma and DLBCL cell lines. We identified the TGFβ-SMAD4 pathway as an important mediator of resistance to selinexor in multiple myeloma cells. Moreover, higher activity of this pathway correlated with prolonged progression-free survival in multiple myeloma patients treated with selinexor, indicating that the TGFβ-SMAD4 pathway is a potential biomarker predictive of therapeutic outcome. In addition, we identified ASB8 (ankyrin repeat and SOCS box containing 8) as a shared modulator of selinexor sensitivity across all tested cancer types, with both ASB8 knockout and overexpression resulting in selinexor hypersensitivity. Mechanistically, we showed that ASB8 promotes selinexor-induced proteasomal degradation of XPO1. This study provides insight into the genetic factors that influence response to selinexor treatment and could support both the development of predictive biomarkers as well as new drug combinations. - Source: PubMed
Publication date: 2023/01/31
Kwanten BertDeconick TineWalker ChristopherWang FengLandesman YosefDaelemans Dirk - MicroRNAs play important roles in the pathogenesis of human diseases by regulating target gene expression in specific cells or tissues. Previously, we identified microRNA 452 (MIR452), which was specifically up-regulated in early stage human colorectal cancer (CRC) tissue. - Source: PubMed
Publication date: 2021/01/04
Mo Ji-SuChae Soo-Cheon