BIRC5 Human

What is BIRC5 and what are its key structural components?

BIRC5 (survivin) is a 16.5 kDa monomer protein consisting of 142 amino acid residues, encoded by the BIRC5 gene located on human chromosome 17q25.3. As a member of the inhibitor of apoptosis proteins (IAPs) family, it contains a baculoviral IAP repeat (BIR) domain that enables binding to caspases and a C-terminal ubiquitin ligase domain responsible for posttranslationally attaching ubiquitin to target proteins . The protein's structural elements are critical for its dual functionality in apoptosis inhibition and cell cycle regulation, distinguishing it from other IAP family members such as XIAP, cIAP1, cIAP2, Livin, and Apollon .

How does BIRC5 expression differ between normal and cancerous tissues?

Bioinformatics analyses across multiple databases including Oncomine, GEPIA, and UALCAN consistently demonstrate that BIRC5 exhibits significantly higher expression in most human cancers compared to their normal tissue counterparts . This differential expression pattern has been particularly well-documented in adrenocortical carcinoma (ACC), kidney renal clear cell carcinoma (KIRC), low-grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD) . The overexpression phenomenon is not random but appears to be a common characteristic across diverse cancer types, suggesting a fundamental role in oncogenesis rather than a tissue-specific aberration.

How does BIRC5 influence the tumor immune microenvironment?

BIRC5 expression has been demonstrated to significantly impact immune cell infiltration in the tumor microenvironment across multiple cancer types . In hepatocellular carcinoma (HCC), BIRC5 functions as a potential biomarker and inducer of intratumor infiltration of myeloid-derived suppressor cells (MDSCs), which subsequently leads to T cell exclusion or dysfunction . The relationship between BIRC5 and immune cells is bidirectional and complex, with TIMER database analysis revealing significant correlations between BIRC5 expression and various immune cell populations, particularly in low-grade glioma (LGG) where this relationship strongly impacts cumulative survival rates .

When investigating this phenomenon, researchers should employ both computational approaches (using tools like TIMER) and experimental validation (flow cytometry, single-cell RNA sequencing) to comprehensively assess how BIRC5 modulates specific immune cell subtypes including M-MDSCs and PMN-MDSCs, which have distinct roles in creating immunosuppressive environments .

What mechanisms link BIRC5 to cancer development and progression?

Functional network analysis reveals that BIRC5 and its interactive genes participate primarily in four critical pathways: apoptosis inhibition, cell division promotion, cell cycle regulation, and cancer pathway activation . Beyond its well-characterized anti-apoptotic function, BIRC5 contributes to cancer progression through:

• Chemoresistance development through caspase inhibition

• Metastasis promotion via cell mobility enhancement

• Tumor progression through sustained proliferative signaling

• Immunosuppressive microenvironment creation through MDSC recruitment

To effectively study these mechanisms, researchers should design experiments that can distinguish between these various functions, potentially using domain-specific mutants or targeted inhibitors that disrupt specific protein-protein interactions rather than global BIRC5 knockdown approaches.

What is the potential role of BIRC5 in stem cell biology?

Research suggests BIRC5 may play a significant role in maintaining pluripotency and regulating differentiation of human stem cells . Studies conducted at the Medical University of Lublin examined BIRC5 expression in various stem cell populations, including hematopoietic stem cells mobilized from peripheral blood . The differential expression of BIRC5 during stem cell differentiation processes suggests it may function as a molecular switch in cellular fate determination.

Investigators exploring this area should consider employing differentiation assays coupled with temporal BIRC5 expression analysis to establish causal relationships between BIRC5 levels and stem cell state transitions. Single-cell analysis approaches may be particularly valuable for capturing heterogeneity in BIRC5 expression across stem cell populations at different differentiation stages.

What bioinformatics tools and databases are most valuable for BIRC5 expression analysis?

Based on comprehensive research methodologies, the optimal bioinformatics approach for BIRC5 research involves integrating multiple databases to achieve robust and reproducible findings . A recommended analytical pipeline includes:

• Oncomine database for initial differential expression analysis between cancer and normal tissues

• GEPIA, UALCAN, and DriverDBv3 for survival analysis and clinical correlation

• GeneMANIA for protein-protein interaction network mapping

• WebGestalt for functional enrichment and pathway analysis

• TIMER for immune infiltration correlation studies

This multi-database approach provides cross-validation of findings and minimizes platform-specific biases. Researchers should be aware that discrepancies between databases can occur and should be addressed through statistical meta-analysis or experimental validation of key findings.

How can researchers effectively produce and validate recombinant BIRC5 for functional studies?

Production of recombinant human BIRC5 protein involves a multi-step process that requires careful optimization . Based on established protocols:

• Gene cloning: Insert the BIRC5 gene (coding for amino acids 1-142) into an expression vector containing an N-terminal 6xHis-SUMO tag

• Transformation: Transform the recombinant vector into an appropriate E. coli strain optimized for protein expression

• Expression induction: Culture transformed bacteria and induce protein expression under optimized conditions

• Protein purification: Lyse cells and purify the BIRC5 protein using affinity chromatography

• Quality control: Validate protein purity (>90%) using SDS-PAGE and confirm functionality through activity assays

For functional validation, researchers should perform binding assays with known BIRC5 interacting partners and assess the recombinant protein's ability to inhibit apoptosis in cell-based systems. The inclusion of proper controls, including inactive mutants, is essential for confirming specificity of observed effects.

What experimental approaches best reveal BIRC5's role in MDSCs and immune regulation?

To investigate BIRC5's immunoregulatory functions, particularly its effects on MDSCs in the tumor microenvironment, researchers should implement a multi-faceted experimental strategy :

• In silico analysis: Begin with bioinformatics correlation of BIRC5 expression with immune cell signatures using tools like TIMER

• Ex vivo characterization: Isolate MDSCs from patient samples or animal models and analyze BIRC5 expression levels via flow cytometry and qPCR

• Functional assessments: Evaluate the immunosuppressive capacity of MDSCs with varying BIRC5 expression through T cell proliferation and cytokine production assays

• Mechanistic studies: Conduct gain and loss of function experiments to determine whether BIRC5 directly affects MDSC expansion, recruitment, or activation

• Therapeutic targeting: Test BIRC5-targeting strategies (inhibitors, antibodies, or genetic approaches) for their ability to reverse MDSC-mediated immunosuppression

Researchers should distinguish between polymorphonuclear-MDSCs (PMN-MDSCs) and monocytic-MDSCs (M-MDSCs) in their analyses, as these subsets may have different relationships with BIRC5 expression and distinct suppressive mechanisms .

How does BIRC5 expression correlate with clinical parameters in cancer patients?

BIRC5 expression exhibits significant correlations with multiple clinicopathological parameters that vary by cancer type . Key relationships include:

• TP53 mutation status: Differential BIRC5 expression patterns are observed between TP53-mutant and wild-type tumors

• Tumor grade: Higher-grade tumors generally show elevated BIRC5 expression compared to lower-grade counterparts

• Disease stage: Advanced-stage cancers typically demonstrate increased BIRC5 expression relative to early-stage disease

• Metastatic status: Primary tumors that develop metastasis often express higher levels of BIRC5

When analyzing these correlations, researchers should employ multivariate statistical approaches to account for confounding variables and potential interactions between clinical parameters. It's also advisable to perform subgroup analyses based on molecular subtypes within each cancer type, as BIRC5's clinical correlations may vary across different molecular contexts.

What therapeutic strategies targeting BIRC5 show the most promise in cancer research?

Multiple BIRC5-targeting therapeutic approaches have been developed and show varying degrees of promise in preclinical and clinical research :

When evaluating these approaches, researchers should consider combining BIRC5 targeting with immune checkpoint inhibitors, particularly in cancers where BIRC5 expression correlates with immunosuppressive microenvironments . The therapeutic strategy should be tailored to the specific cancer type and molecular context, as the role of BIRC5 may vary across different malignancies.

How can BIRC5 analysis be integrated into precision oncology approaches?

Integration of BIRC5 analysis into precision oncology frameworks requires a multi-omics approach :

• Expression profiling: Quantify BIRC5 mRNA and protein levels in patient samples through RNA-seq and immunohistochemistry

• Genetic analysis: Assess BIRC5 gene amplification, mutations, and promoter modifications

• Pathway integration: Evaluate BIRC5 in the context of related pathway alterations, particularly cell cycle and apoptosis networks

• Immune contextualization: Analyze BIRC5 expression in relation to tumor immune infiltration patterns

• Multi-biomarker panels: Incorporate BIRC5 into prognostic and predictive panels alongside other established markers

This integrated approach provides more clinically relevant information than single-marker analysis. Researchers should develop decision algorithms that incorporate BIRC5 status alongside other molecular and clinical parameters to guide therapeutic decisions and clinical trial enrollment. The significant correlation between BIRC5 expression and patient outcomes in specific cancer types supports its potential utility as a stratification marker for clinical trials of targeted therapies .

What are the knowledge gaps in understanding BIRC5's regulatory mechanisms?

Despite extensive research, several critical aspects of BIRC5 regulation remain incompletely understood :

• The precise signaling pathways, cytokines, and chemokines through which BIRC5 impacts MDSC amplification and infiltration in tumor tissues

• The differential roles of BIRC5 across cancer subtypes and their relationship to genomic alterations beyond TP53 mutations

• The mechanisms regulating BIRC5 expression in stem cells and their relationship to differentiation pathways

• The post-translational modifications that affect BIRC5 protein stability and function in different cellular contexts

• The feedback mechanisms between BIRC5 expression and immune cell populations in the tumor microenvironment

Addressing these knowledge gaps will require integrated approaches combining single-cell technologies, spatial transcriptomics, and functional genomics to elucidate the context-specific roles of BIRC5 across different biological systems.

How might advances in single-cell analysis enhance our understanding of BIRC5 function?

Single-cell technologies offer unprecedented opportunities to resolve the heterogeneous expression and function of BIRC5 across cell populations :

• Single-cell RNA sequencing can reveal cell type-specific expression patterns of BIRC5 within complex tissues

• Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) can correlate BIRC5 expression with cell surface markers defining functional states

• Single-cell ATAC-seq can identify regulatory elements controlling BIRC5 expression in specific cellular contexts

• Spatial transcriptomics can map BIRC5 expression patterns within the tumor microenvironment and correlate with immune cell distributions

• Single-cell proteomics can assess the relationship between BIRC5 protein levels and activation states of signaling pathways

These approaches will be particularly valuable for understanding BIRC5's role in immune regulation and stem cell biology, where cell population heterogeneity is a significant confounding factor in traditional bulk analysis methods .

What novel collaborative approaches could accelerate BIRC5 research?

Advancing BIRC5 research will benefit from multidisciplinary collaborative frameworks that integrate expertise across several domains :

• Computational-experimental partnerships: Combine bioinformatics predictions with targeted experimental validation

• Basic-clinical research integration: Connect mechanistic findings to clinical observations through translational research

• Multi-cancer consortia: Compare BIRC5 functions across cancer types to identify common and distinct mechanisms

• Technology-biology collaborations: Apply cutting-edge methodologies (CRISPR screens, proteomics, structural biology) to answer fundamental questions about BIRC5 biology

• Public-private partnerships: Accelerate therapeutic development through collaborative efforts between academic institutions and pharmaceutical companies

Such collaborative approaches will help address the complexity of BIRC5 biology and accelerate the translation of basic findings into clinical applications. The multifaceted role of BIRC5 in cancer, immunity, and stem cell biology makes it an ideal target for integrated research programs that span traditional disciplinary boundaries.