STEAP4 Human
Description
Product Specs
Q&A
What is STEAP4 and what is its primary function in human cells?
STEAP4 functions as a metalloreductase involved in iron and copper homeostasis and plays a potentially important role in cellular response to inflammatory stress. Research indicates that STEAP4 helps protect cells from damage and maintains normal metabolic function, particularly in metabolically oriented cells such as adipocytes, hepatocytes, and pancreatic islet cells . These cells struggle to maintain function in iron or copper overloaded states, suggesting STEAP4's role in metal homeostasis is critical to maintaining cellular homeostasis and preventing metabolic disease .
Methodological approach: To study STEAP4's basic function, researchers typically utilize gene expression analysis in various cell types, metal uptake/reduction assays, and knockout models to observe metabolic and inflammatory phenotypes.
How do genetic variations in STEAP4 correlate with human metabolic disorders?
Genome-wide association studies have linked various mutations in STEAP4 with the development of metabolic disorders including obesity, metabolic syndrome, and type 2 diabetes . Specific genetic variants in STEAP4 have been associated with putative defects in the acute insulin response to glucose in type 2 diabetes (T2D) .
Methodological approach: Researchers investigating genetic associations should employ sequencing approaches combined with metabolic phenotyping and consider both common variants and rare mutations that might affect STEAP4 function or expression.
How does STEAP4 expression vary with demographic and clinical parameters?
Research shows STEAP4 expression correlates with several clinical parameters:
-
BMI correlation: STEAP4 showed reduced islet expression with increasing BMI among non-diabetic donors (P<0.05) .
-
Glycemic control: In T2D donors, STEAP4 showed reduced islet expression with increasing HbA1c .
-
Sex differences: STEAP4 expression was marginally higher in islets from female donors compared to male donors (Female: 4.4 +/-0.3 vs Male: 3.6 +/-0.4, P<0.10) . This sex difference was more pronounced in some study cohorts (Female: 2.6+/-0.5 vs Male: 0.7+/-0.2, P<0.01) .
-
Age: No significant correlation was observed between age and STEAP4 expression in the studies reviewed .
Methodological approach: When designing studies to examine STEAP4 expression, researchers should stratify their analysis by sex, BMI, and disease status, and employ quantitative PCR with appropriate housekeeping gene normalization.
How is STEAP4 expression regulated by inflammatory signals?
STEAP4 expression is modulated by inflammatory cytokines, hormones, and other indicators of cellular stress . Islets from non-diabetic donors exposed overnight to 5ng/ml IL-1β displayed increased STEAP4 expression, consistent with STEAP4 upregulation by inflammatory signaling . Additionally, STEAP4 is specifically induced by IL-17-producing Th17 cells in neuroinflammatory conditions .
Methodological approach: To study inflammatory regulation of STEAP4, researchers should design in vitro stimulation experiments with dose-response curves for various cytokines, and validate findings in vivo using appropriate disease models.
| Donor Group | STEAP4 Expression | WBC Count (×1000) | Notes |
|---|---|---|---|
| T2D Donors | 3.1±0.7 | 24.7±2.6 | Higher inflammation markers |
| Non-T2D Donors | Lower (values varied) | Lower (specific values varied) | Lower inflammation markers |
What is the role of STEAP4 in pancreatic islet function and type 2 diabetes?
STEAP4 appears to have tissue-specific roles in pancreatic islets that may be relevant to T2D pathophysiology. Among T2D donors in some cohorts, islet insulin expression was reduced while STEAP4 expression was increased compared to non-diabetic donors . This suggests potential compensatory upregulation of STEAP4 in response to metabolic stress or inflammation in T2D.
Methodological approach: Researchers investigating STEAP4 in islet biology should employ both human islets from donors with and without T2D and consider designing islet-specific knockout models to elucidate tissue-specific functions.
How does STEAP4 contribute to neuroinflammatory conditions like multiple sclerosis?
STEAP4 functions as a key effector molecule that participates in the pathogenesis of Th17-mediated neuroinflammation in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis . STEAP4 knockout mice displayed delayed onset and reduced severity of EAE induced by active immunization . Importantly, STEAP4 was specifically induced in the spinal cord of EAE mice that received Th17 cells but not Th1 cells, and STEAP4 deficiency protected from Th17-induced but not Th1-induced EAE .
Methodological approach: Researchers studying STEAP4 in neuroinflammation should utilize both active immunization and passive transfer EAE models, and consider cellular source-specific conditional knockout approaches.
What animal and cellular models are most appropriate for studying STEAP4 function?
Based on the literature, several experimental models have proven valuable:
-
Global STEAP4 knockout mice: Useful for studying systemic effects of STEAP4 deficiency .
-
Conditional STEAP4 knockout models: These allow tissue-specific deletion, such as Nestin-Cre STEAP4 fl/fl mice for CNS-specific studies .
-
Human islet isolation: Enables direct study of STEAP4 in primary human tissue .
-
Cytokine stimulation assays: For investigating STEAP4 regulation by inflammatory mediators .
Methodological approach: When designing studies, researchers should consider the specific hypothesis being tested and select the model system that best isolates the role of STEAP4 in the relevant tissue or disease process.
How can researchers effectively measure functional outcomes of STEAP4 alteration?
To assess STEAP4's functional impact, researchers should evaluate:
-
Metal homeostasis: Measure iron and copper levels and oxidation states in relevant tissues.
-
Inflammatory markers: Assess cytokine/chemokine expression profiles in affected tissues .
-
Tissue pathology: Examine histological changes such as demyelination in neuroinflammatory models .
-
Metabolic parameters: Measure glucose homeostasis, insulin sensitivity, and lipid metabolism in metabolic disorder models.
Methodological approach: Multi-parameter assessment combining molecular, cellular, and physiological readouts provides the most comprehensive understanding of STEAP4 function.
How might STEAP4 interact with other metalloreductases and metal transport systems?
While STEAP4's role in metal homeostasis is established, its interactions with other metal regulatory proteins remain poorly characterized. Understanding these relationships would provide insights into redundant or complementary functions.
Methodological approach: Researchers should consider employing proteomics approaches to identify STEAP4 interaction partners, combined with multi-gene knockout or knockdown studies to reveal functional relationships.
What are the unresolved questions regarding tissue-specific roles of STEAP4?
STEAP4 appears to have context-dependent functions in different tissues. In CNS resident cells, STEAP4 promotes Th17 cell-induced autoimmune encephalomyelitis , while in metabolic tissues it may have protective functions against inflammatory damage .
Methodological approach: To resolve these apparent contradictions, researchers should utilize tissue-specific conditional knockout models combined with cell type-specific gene expression analysis and different disease challenge models.
How might therapeutic targeting of STEAP4 be developed for metabolic or inflammatory diseases?
Methodological approach: Drug discovery efforts should consider:
-
Tissue-specific delivery approaches
-
Modulators rather than complete inhibitors of STEAP4 function
-
Sex-specific considerations given the observed differences in expression
-
Combination approaches targeting both STEAP4 and related inflammatory pathways
Product Science Overview
STEAP (Six-Transmembrane Epithelial Antigen of Prostate) family proteins are a group of metalloreductases involved in metal ion metabolism. The family includes four members: STEAP1, STEAP2, STEAP3, and STEAP4. These proteins are unique to mammals and play significant roles in various biological processes, including molecular trafficking, cell proliferation, and apoptosis .
STEAP4, also known as Six-Transmembrane Epithelial Antigen of Prostate 4, is a protein encoded by the STEAP4 gene in humans. It is highly expressed in several tissues, including adipose tissue, bone marrow, heart, lung, placenta, and prostate . STEAP4 is known for its iron reductase activity, which contributes to the regulation of reactive oxygen species (ROS) levels within cells .
STEAP4 functions primarily as a metalloreductase, facilitating the reduction of iron and copper ions. This activity is crucial for maintaining metal homeostasis within cells. The protein’s role in reducing iron and copper ions is mediated by its conserved histidine residues, which bind to an intramembrane heme group .
In addition to its metalloreductase activity, STEAP4 is involved in various cellular processes:
- Cell Proliferation and Apoptosis: STEAP4 influences cell proliferation and apoptosis through its impact on ROS levels. Increased ROS levels can lead to oxidative stress, which in turn affects cell survival and proliferation .
- Cancer: STEAP4 is overexpressed in several types of cancers, including prostate, bladder, and gastric cancers. Its expression levels are associated with cancer progression and patient prognosis .
Human recombinant STEAP4 is produced using recombinant DNA technology, which involves inserting the STEAP4 gene into a suitable expression system, such as bacteria or mammalian cells. This allows for the production of large quantities of the protein for research and therapeutic purposes.
The study of STEAP4 has significant implications for understanding metal metabolism and its role in various diseases. Some key applications include:
- Cancer Research: Given its overexpression in several cancers, STEAP4 is a potential biomarker and therapeutic target. Research is ongoing to develop STEAP4-targeted therapies for cancer treatment .
- Metabolic Disorders: STEAP4’s role in metal ion metabolism makes it a candidate for studying metabolic disorders related to iron and copper homeostasis .
