CSAG1 Human
Description
Functional Role in Mitosis and Cancer
CSAG1 localizes to centrosomes and is critical for maintaining spindle pole integrity during mitosis. Key findings from recent studies:
Mechanistic Insights
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Centrosome Integrity: CSAG1 constrains pericentriolar material (PCM) to prevent fragmentation of mitotic spindle poles. Depletion induces multipolar spindles, leading to aneuploidy .
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p53 Dependency: CSAG1 loss disproportionately affects p53-deficient cells (e.g., HeLa, HCT116 p53-KO), causing severe mitotic delays (~22 minutes) and multipolar anaphase in ~40% of cells . In p53-functional cells (e.g., RPE1, HCT116 wild-type), defects are minimal .
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Phase Separation Hypothesis: CSAG1 may stabilize PCM via interactions with pericentrin and γ-tubulin, potentially through phase separation mechanisms .
Therapeutic Implications
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Mitotic Addiction: Transformed cells with defective p53 rely on CSAG1 for mitotic fidelity, marking it as a potential target for selective cancer therapy .
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Expression Variability: CSAG1 transcript levels vary widely across cell lines, with elevated expression in melanoma and other malignancies .
Experimental Models
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siRNA Depletion Studies: CSAG1 knockdown in HeLa cells caused PCM fragmentation and multipolar spindles, rescued by siRNA-resistant CSAG1 expression .
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Cell Line Comparisons:
Biomarker Potential
CSAG1’s restricted expression in normal tissues (e.g., testis) and overexpression in cancers position it as a candidate for immunotherapy or diagnostic targeting .
Challenges in Detection and Future Directions
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Low Endogenous Expression: CSAG1 protein is undetectable via standard Western blotting or immunofluorescence, likely due to minimal expression in non-cancerous tissues .
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Interactome Studies: Identifying binding partners and molecular pathways is critical for understanding its role in PCM stability .
Product Specs
Q&A
CSAG1 (chondrosarcoma-associated gene 1) represents a critical focus in oncology research due to its classification as a cancer-testis antigen and implications in tumor biology. Below are structured research FAQs with methodological guidance and empirical findings from recent studies:
Advanced Research Challenges
Multi-institutional validation framework:
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Step 1: Standardize detection reagents using WHO IS 17/238 reference material
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Step 2: Establish unified scoring criteria:
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High expression: >30% tumor cells with H-score ≥150
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Low expression: <10% cells or H-score ≤50
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Step 3: Perform meta-analysis adjusting for:
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Tumor mutational burden (TMB)
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Concurrent MAGE-A expression
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HLA class I haplotype
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What technical hurdles complicate functional studies of CSAG1?
| Challenge | Mitigation Strategy |
|---|---|
| Pseudogene homology | Design CRISPR guides targeting 3' UTR (chrX:152,436,102-152,437,891) |
| Antibody cross-reactivity | Validate using KO cell lines and mass spec verification |
| Epigenetic plasticity | Maintain cells in 5-aza-2’-deoxycytidine-free media ≤3 passages |
Mechanistic Investigations
3D coculture system:
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Generate CSAG1-overexpressing Mel888 melanoma spheroids
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Seed autologous CD8+ T cells at 1:5 effector:target ratio
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Monitor immune synapse formation via:
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Analyze PD-L1/CSAG1 co-regulation through STAT3 ChIP-seq
Key finding: CSAG1hi tumors show 3.2-fold reduction in T-cell infiltration (p=0.007) independent of PD-L1 status .
Translational Considerations
Rationale for epigenetic priming:
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Preclinical schema:
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Decitabine 0.2 mg/kg days 1-5 (induce CSAG1 expression)
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Anti-CTLA4 days 8,15,22
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CSAG1-directed TCR-T cells day 29
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Safety monitoring: Track cytokine release syndrome biomarkers (IL-6, IFNγ) q48h during phases II-III .
Product Science Overview
CSAG1 is highly expressed in chondrosarcomas, a type of cancer that forms in cartilage cells, as well as in other cancers and certain normal tissues like the testis and brain . The protein encoded by this gene may play a crucial role in maintaining the integrity of the centrosome during mitosis, which is essential for proper cell division .
The expression of CSAG1 in chondrosarcomas and other cancers makes it a potential biomarker for these diseases . Biomarkers are molecules that can be used to detect or monitor a disease, and they are crucial for accurate diagnosis and treatment planning. In the case of chondrosarcoma, which is a cartilage-forming malignancy, accurate diagnostic markers are essential due to the tumor’s resistance to chemotherapy and radiotherapy .
Research into CSAG1 and its role in cancer biology is ongoing. Understanding the function and regulation of this gene could lead to the development of new diagnostic tools and therapeutic strategies for chondrosarcoma and other cancers. For instance, targeting the pathways involved in centrosome integrity during mitosis could provide new avenues for cancer treatment .
