• Adipocyte Differentiation
• Circular RNA
• Goat
• STEAP Family Member 4

• 32072723 National Natural Science Foundation of China
• 2022JDTD0030 Sichuan Science and Technology Program
• 2024CXTD12 Southwest Minzu University

• Colorectal cancer
• Gastric cancer
• Gastrointestinal cancer
• Hepatocellular carcinoma
• Inflammation
• Six transmembrane epithelial antigens of the prostate

• Gastrointestinal cancer
• Inflammation
• Six transmembrane epithelial antigens of the prostate

• AKT
• Chemotherapy resistance
• Hepatocellular carcinoma
• STEPA4

Despite recent therapeutic advances in the treatment of prostate cancer, metastatic castration-resistant prostate cancer continues to cause significant morbidity and mortality. New research into highly expressed proteins in metastatic castration-resistant prostate cancer shows that Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) are significant drivers of prostate cancer aggressiveness and metastasis. STEAP1, in particular, is highly expressed on the plasma membrane of prostate cancer cells and has received significant attention as a potential therapeutic target. This review highlights what is known about STEAP1–4 and identifies knowledge gaps that require further research.

Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1–4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1–4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1–4 to provide context for past and current efforts to translate STEAP1–4 into the clinic.

• T-cell-engaging antibody
• biomarker
• cancer vaccine
• immunotherapy
• prostate cancer
• six-transmembrane epithelial antigen of the prostate

Healthy adipose tissue is crucial to maintain normal energy homeostasis. Little is known about the role of murine double minute 2 (MDM2), an E3 ubiquitin ligase and has been highlighted in oncopathology, in adipose tissue. Our results indicated that MDM2 expression was associated with nutritional status. Mdm2 adipocyte-specific knock-in (Mdm2-AKI) mice exhibited exacerbated weight gain, insulin resistance, and decreased energy expenditure. Meanwhile, chronic high-fat diet (HFD) exposure caused obvious epididymal white adipose tissue (eWAT) dysfunction, such as senescence, apoptosis, and chronic inflammation, thereby leading to hepatic steatosis in Mdm2-AKI mice. Mechanically, MDM2 could interact with six-transmembrane epithelial antigen of prostate 4 (STEAP4) and inhibit STEAP4 expression through ubiquitin-mediated STEAP4 degradation. Thereinto, the K18 and K161 sites of STEAP4 were ubiquitin-modificated by MDM2. Finally, STEAP4 restoration in eWAT of Mdm2-AKI mice on a HFD rescued MDM2-induced adipose dysfunction, insulin resistance, and hepatic steatosis. Summary, the MDM2-STEAP4 axis in eWAT plays an important role in maintaining healthy adipose tissue function and improving hepatic steatosis.

•

Murine double minute 2 (MDM2) overexpression intensifies high-fat diet-induced adipose tissue dysfunction

• Atherosclerosis
• Glucose spikes
• Inflammation
• Monocytes
• STAMP2
• Western diet

• NADPH
• NF-κB
• NMRAL1
• STAMP2
• diabetic cardiomyopathy

• National Natural Science Foundation of China
• Science and Technology Planning Project of Wenzhou, Wenzhou, China

Sepsis is a systemic disease characterized by extensive inflammatory responses and impaired organ function, which are characteristics that make it easily missed and complex to treat. A large number of laboratory and clinical studies on the diagnosis and treatment of sepsis have been continuously carried out, confirming the importance of mitochondrial function during the development of sepsis. STEAP4 is an important metalloreductase in mitochondria, which is involved in the biogenesis and respiratory chain of mitochondria. The role of STEAP4 in inflammation remains controversial. Research in this field may contribute to the development of new diagnostic and treatment options for sepsis.

The expression of STEAP4 was measured in the peripheral blood of patients with severe sepsis and compared with healthy controls. Cell and mouse inflammatory models were established to detect the expression of STEAP4 and other inflammatory cytokines.

(I) The expression of STEAP4 in the peripheral blood of patients with severe sepsis is higher than that of healthy volunteers (P<0.01), which is related to the SOFA score and transaminase. (II) STEAP4 has a certain predictive effect on the outcome of patients [area under curve (AUC) =0.696, P<0.05, 95% CI: 0.528 to 0.833]. (III) Inflammation led to increased expression of STEAP4 gene in RAW264.7 cells and mouse liver tissue.

The expression of STEAP4 is elevated in the early stage of sepsis and the degree of its elevation can be used to predict the clinical outcome of sepsis patients.

• STEAP4
• biomarker
• sepsis

Pyrrolizidine alkaloids (PAs) are secondary plant metabolites synthesized by a wide range of plants as protection against herbivores. These toxins are found worldwide and pose a threat to human health. PAs induce acute effects like hepatic sinusoidal obstruction syndrome and pulmonary arterial hypertension. Moreover, chronic exposure to low doses can induce cancer and liver cirrhosis in laboratory animals. The mechanisms causing hepatotoxicity have been investigated previously. However, toxic effects in the lung are less well understood, and especially data on the correlation effects with individual chemical structures of different PAs are lacking. The present study focuses on the identification of gene expression changes in vivo in rat lungs after exposure to six structurally different PAs (echimidine, heliotrine, lasiocarpine, senecionine, senkirkine, and platyphylline). Rats were treated by gavage with daily doses of 3.3 mg PA/kg bodyweight for 28 days and transcriptional changes in the lung and kidney were investigated by whole-genome microarray analysis. The results were compared with recently published data on gene regulation in the liver. Using bioinformatics data mining, we identified inflammatory responses as a predominant feature in rat lungs. By comparison, in liver, early molecular consequences to PAs were characterized by alterations in cell-cycle regulation and DNA damage response. Our results provide, for the first time, information about early molecular effects in lung tissue after subacute exposure to PAs, and demonstrates tissue-specificity of PA-induced molecular effects.

• Gene expression
• Inflammation
• Lung
• Pyrrolizidine alkaloids
• Transcriptomics

Six-transmembrane protein of prostate (Stamp2) protects from diabetes and atherosclerosis in mice via anti-inflammatory mechanisms. As chronic inflammation is a hallmark of pulmonary arterial hypertension (PAH), we investigated the role of Stamp2. Stamp2 expression was substantially reduced in the lung of humans with idiopathic PAH, as well as in experimental PAH. In Stamp2-deficient mice, hypoxia modestly aggravated pulmonary vascular remodeling and right ventricular pressure compared to WT. As endothelial cell (EC) and pulmonary arterial smooth muscle cell (PASMC) phenotypes drive remodeling in PAH, we explored the role of Stamp2. Knock-down of Stamp2 in human EC neither affected apoptosis, viability, nor release of IL-6. Moreover, Stamp2 deficiency in primary PASMC did not alter mitogenic or migratory properties. As Stamp2 deficiency augmented expression of inflammatory cytokines and numbers of CD68-positive cells in the lung, actions of Stamp2 in macrophages may drive vascular remodeling. Thus, PASMC responses were assessed following treatment with conditioned media of primary Stamp2^−/− or WT macrophages. Stamp2^−/− supernatants induced PASMC proliferation and migration stronger compared to WT. A cytokine array revealed CXCL12, MCP-1 and IL-6 as most relevant candidates. Experiments with neutralizing antibodies confirmed the role of these cytokines in driving Stamp2’s responses. In conclusion, Stamp2 deficiency aggravates pulmonary vascular remodeling via cross-talk between macrophages and PASMC. Despite a substantial pro-inflammatory response, the hemodynamic effect of Stamp2 deficiency is modest suggesting that additional mechanisms apart from inflammation are necessary to induce severe PAH.

• Inflammation
• Macrophages
• Pulmonary hypertension
• Stamp2
• Vascular remodeling

• Histamine-releasing factor (HRF)
• Human basophils
• Human eosinophils
• Inducible-transgenic mouse
• Interleukin 13
• Interleukin 4
• Mast cells
• Src homology 2 domain-containing inositol 5’ phosphatase (SHIP-1)
• Translationally controlled tumor protein (TCTP)

• Animals
• Asthma/drug therapy
• Asthma/metabolism
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/biosynthesis
• Histamine/metabolism
• Humans
• Hypersensitivity/drug therapy
• Hypersensitivity/metabolism
• Molecular Targeted Therapy
• Tumor Protein, Translationally-Controlled 1

• Adipocyte
• ER stress
• Gene expression
• Iron reductase
• Protein translocation
• STAMP2

• Adipocytes/metabolism
• Adipocytes/pathology
• Animals
• Cells, Cultured
• Endoplasmic Reticulum Stress/drug effects
• Inflammation/chemically induced
• Inflammation/metabolism
• Membrane Proteins/analysis
• Membrane Proteins/deficiency
• Membrane Proteins/metabolism
• Mice
• RNA, Messenger/analysis
• Thapsigargin/pharmacology
• Tumor Necrosis Factor-alpha/pharmacology

• R90 DK071507 NIDDK NIH HHS

Six transmembrane protein of prostate 2 (STAMP2) is a critical modulator of inflammation and metabolism in adipose tissue. There are no data on the expression of STAMP2 in chronic kidney disease, which is an inflammatory disease related to metabolic disorders. This study aimed to investigate STAMP2 expression in the kidney and heart in 5/6 nephrectomy (Nx) rats, and the effect of omega-3 fatty acid (FA) on STAMP2 expression. Male Sprague Dawley rats were divided into three groups: sham control (0.9% saline), 5/6 Nx (0.9% saline), and 5/6 Nx treated with omega-3 FA (300 mg per kg per day by gastric gavage). The expression of STAMP2 in the kidney and heart were examined by western blotting. Serum creatinine levels were higher in 5/6 Nx rats than in controls. Compared with sham controls, the expression of IκB, NF-κB, NOX4, SREBP-1, and LXR were upregulated and STAMP2 and phosphorylated-AMPK expression were downregulated in the kidney and heart of 5/6 Nx rats. Omega-3 FA supplementation prevented these changes in biomarkers related to inflammation and metabolic lipid disorders. Omega 3-FA supplementation induced the upregulation of STAMP2 protein in 5/6 Nx rats, which was associated with an attenuation of inflammation- and metabolic disease-related markers.

• STAMP2
• heart
• kidney
• omega-3 fatty acid

• AMP-Activated Protein Kinase Kinases
• Animals
• Creatinine/blood
• Disease Models, Animal
• Fatty Acids, Omega-3/pharmacology
• I-kappa B Proteins/biosynthesis
• Kidney/metabolism
• Kidney/pathology
• Kidney/surgery
• Kidney Failure, Chronic/etiology
• Kidney Failure, Chronic/metabolism
• Kidney Failure, Chronic/pathology
• Liver X Receptors/biosynthesis
• Male
• Membrane Proteins/biosynthesis
• Myocardium/metabolism
• Myocardium/pathology
• NADPH Oxidase 4/biosynthesis
• NF-kappa B/biosynthesis
• Nephrectomy
• Protein Kinases/biosynthesis
• Rats
• Rats, Sprague-Dawley
• Sterol Regulatory Element Binding Protein 1/biosynthesis

Enzymes of the six-transmembrane epithelial antigen of the prostate (STEAP) family reduce Fe³⁺ and Cu²⁺ ions to facilitate metal-ion uptake by mammalian cells. STEAPs are highly upregulated in several types of cancer, making them potential therapeutic targets. However, the structural basis for STEAP-catalyzed electron transfer through an array of cofactors to metals at the membrane luminal side remains elusive. Here, we report cryo-electron microscopy structures of human STEAP4 in absence and presence of Fe³⁺-NTA. Domain-swapped, trimeric STEAP4 orients NADPH bound to a cytosolic domain onto axially aligned flavin-adenine dinucleotide (FAD) and a single b-type heme that cross the transmembrane-domain to enable electron transfer. Substrate binding within a positively charged ring indicates that iron gets reduced while in complex with its chelator. These molecular principles of iron reduction provide a basis for exploring STEAPs as therapeutic targets.

Enzymes of the six-transmembrane epithelial antigen of the prostate (STEAP) family reduce Fe3+ and Cu2+ ions to facilitate metal-ion uptake by mammalian cells. Here, authors employ single-particle cryo-EM to gain insights into the molecular principles of iron reduction by human STEAP4 .

• Conformational epitope
• Endosome
• Extracellular loop
• Golgi
• Membrane cholesterol
• Metalloreductase
• Plasma membrane
• STEAP2

Free fatty acids (FFAs), which are elevated with metabolic syndrome, are considered the principal offender exerting lipotoxicity. Few previous studies have reported a causal relationship between FFAs and osteoarthritis pathogenesis. However, the molecular mechanism by which FFAs exert lipotoxicity and induce osteoarthritis remains largely unknown. We here observed that oleate at the usual clinical range does not exert lipotoxicity while oleate at high pathological ranges exerted lipotoxicity through apoptosis in articular chondrocytes. By investigating the differential effect of oleate at toxic and nontoxic concentrations, we revealed that lipid droplet (LD) accumulation confers articular chondrocytes, the resistance to lipotoxicity. Using high fat diet-induced osteoarthritis models and articular chondrocytes treated with oleate alone or oleate plus palmitate, we demonstrated that articular chondrocytes gain resistance to lipotoxicity through protein kinase casein kinase 2 (PKCK2)—six-transmembrane protein of prostate 2 (STAMP2)—and fat-specific protein 27 (FSP27)-mediated LD accumulation. We further observed that the exertion of FFAs-induced lipotoxicity was correlated with the increased concentration of cellular FFAs freed from LDs, whether FFAs are saturated or not. In conclusion, PKCK2/STAMP2/FSP27-mediated sequestration of FFAs in LD rescues osteoarthritic chondrocytes. PKCK2/STAMP2/FSP27 should be considered for interventions against metabolic OA.

Cartilage tissue deals with the stress of exposure to free fatty acids by sequestering the toxic molecules into sub-cellular oil droplets. Young Hyun Yoo from Dong-A University College of Medicine in Busan, South Korea, and coworkers exposed rat cartilage cells to increasing levels of a fatty acid called oleate, a by-product of fat metabolism, and observed that the accumulation of oil droplets conferred resistance to oleate-induced toxicity. In these rat cells and in experiments involving mouse models of osteoarthritis fed a high-fat diet, the researchers then identified three of the protective proteins needed for cartilage tissue to properly quarantine fatty acids into oil droplets. Those proteins — and their connected regulatory networks — could now serve as drug targets for treating metabolic syndrome-associated osteoarthritis.

• Absolute transcription profiles
• Larval development
• Probiotics
• Senegalese sole (Solea senegalensis)
• Shewanella putrefaciens Pdp11 (SpPdp11)

• Animal Feed/analysis
• Animals
• Diet/veterinary
• Fish Proteins/genetics
• Fish Proteins/metabolism
• Flatfishes/genetics
• Flatfishes/growth & development
• Flatfishes/immunology
• Probiotics/pharmacology
• Shewanella putrefaciens/chemistry
• Transcription, Genetic

• STEAP4
• TIARP
• monocytes
• rheumatoid arthritis
• splice variant

• STEAP4
• colorectal cancer
• hypoxia
• inflammatory bowel disease
• mitochondrial iron

• STEAP4
• T2D
• beta-cells
• copper
• cytokines
• iron homeostasis
• iron overload
• islets
• low-grade inflammation

• Animals
• Copper/metabolism
• Homeostasis
• Humans
• Iron/metabolism
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Metabolic Diseases/enzymology
• Metabolic Diseases/genetics
• Metabolic Diseases/metabolism
• Oxidative Stress
• Oxidoreductases/genetics
• Oxidoreductases/metabolism

• R01 DK089182 NIDDK NIH HHS

• Cytokines
• Inflammation
• Iron
• Islets
• Obesity
• Type 2 diabetes

• Adult
• Aged
• Body Mass Index
• Diabetes Mellitus, Type 2/metabolism
• Female
• Glycated Hemoglobin/metabolism
• Humans
• Inflammation/metabolism
• Islets of Langerhans/metabolism
• Male
• Membrane Proteins/metabolism
• Middle Aged
• Obesity/metabolism
• Oxidoreductases/metabolism
• Sex Factors

• R01 DK089182 NIDDK NIH HHS
• R01 DK101803 NIDDK NIH HHS
• I01 BX001733 BLRD VA
• P30 DK097512 NIDDK NIH HHS
• R01 DK093954 NIDDK NIH HHS

TNFα-induced adipose-related protein (TIARP) is a six-transmembrane protein expressed on macrophages, neutrophils and synoviocytes. We reported recently that mice deficient in TIARP (TIARP^−/−) spontaneously develop arthritis and are highly susceptible to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effects of TIARP on neutrophils and fibroblast-like synoviocytes (FLS) have not been elucidated. We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP^−/− mice. Arthritis in TIARP^−/− mice transferred with K/BxN serum was significantly exacerbated compared with WT mice. We characterized the differences in neutrophils between wild-type (WT) and TIARP^−/− mice by DNA microarray. Overexpression of CXCR1 and CXCR2 was noted in TIARP^−/− neutrophils. Neutrophils of TIARP^−/− mice showed strong migration activity, which was markedly facilitated by CXCL2 in vitro and in vivo. Moreover, enhanced production of CXCL2 and IL-6 and cell proliferation was noted in TIARP^−/− TNFα-stimulated FLS. Blockade of IL-6R significantly attenuated serum-transferred TIARP^−/− arthritis with diminished neutrophil recruitment in joints. Our findings suggested that TIARP independently down-regulated CXCL2 and IL-6 production by FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, with resultant reduction of neutrophil migration into arthritic joints.

• 6-transmembrane epithelial antigens of prostate
• CXCL1
• CXCL8
• IL-1
• IL-36
• Pustular skin disorders
• inflammation
• neutrophils
• transcriptomic profiling

• ASC
• STAMP2
• adipogenesis
• lipogenesis
• prostate cancer

• Inflammation
• Ironreductase
• Metabolism
• Prostate cancer
• STAMP
• STEAP

• Animals
• Cell Cycle Proteins
• Cell Differentiation
• Gene Expression Regulation
• Humans
• Inflammation/metabolism
• Membrane Proteins/chemistry
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Metabolic Diseases/metabolism
• Neoplasm Proteins/chemistry
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/metabolism
• Oncogene Proteins/chemistry
• Oncogene Proteins/genetics
• Oncogene Proteins/metabolism
• Oxidoreductases/chemistry
• Oxidoreductases/genetics
• Oxidoreductases/metabolism
• Tissue Distribution

• Gene expression
• Immune system
• Photobacterium damselae subp. damselae
• Retinoic acid
• Senegalese sole Solea senegalensis
• Vitamin

• Animal Feed/analysis
• Animals
• Diet/veterinary
• Dietary Supplements/analysis
• Dose-Response Relationship, Immunologic
• Fish Diseases/immunology
• Fish Diseases/microbiology
• Flatfishes
• Gram-Negative Bacterial Infections/immunology
• Gram-Negative Bacterial Infections/microbiology
• Gram-Negative Bacterial Infections/veterinary
• Immunocompetence/drug effects
• Photobacterium/physiology
• Real-Time Polymerase Chain Reaction/veterinary
• Vitamin A/administration & dosage
• Vitamin A/metabolism
• Vitamins/administration & dosage
• Vitamins/metabolism

• Animals
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Diabetes Mellitus, Experimental/metabolism
• Diabetes Mellitus, Type 2/metabolism
• Factor XIII/genetics
• Factor XIII/metabolism
• Gene Expression Profiling
• Genome-Wide Association Study
• Humans
• Inflammation/metabolism
• Interleukin-1beta
• Interleukin-6
• Islets of Langerhans/metabolism
• Male
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mice
• Oligonucleotide Array Sequence Analysis
• Receptor-Interacting Protein Serine-Threonine Kinase 2
• Receptor-Interacting Protein Serine-Threonine Kinases/genetics
• Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
• Serine Endopeptidases/genetics
• Serine Endopeptidases/metabolism
• Serine Proteases
• Stress, Physiological

• R01 DK089182 NIDDK NIH HHS
• R01 DK085175 NIDDK NIH HHS
• R01DK089182 NIDDK NIH HHS
• R01 DK061628 NIDDK NIH HHS
• HL47902 NHLBI NIH HHS
• HL047890 NHLBI NIH HHS
• HL047887 NHLBI NIH HHS
• HL060919 NHLBI NIH HHS
• UL1 TR000124 NCATS NIH HHS
• R01 HL060944 NHLBI NIH HHS
• K01DK081621 NIDDK NIH HHS
• DK085175 NIDDK NIH HHS
• U01 HL047902 NHLBI NIH HHS
• P30 DK063491 NIDDK NIH HHS
• K01 DK081621 NIDDK NIH HHS
• R01 HL061019 NHLBI NIH HHS
• HL060944 NHLBI NIH HHS
• HL047889 NHLBI NIH HHS
• DK061628 NIDDK NIH HHS
• R01 HL060919 NHLBI NIH HHS
• HL061019 NHLBI NIH HHS

• Steap1
• Steap3
• b-type cytochrome
• copper
• copper transport
• cupric reductase
• ferric reductase
• flavin adenine dinucleotide (FAD)
• iron
• iron metabolism

• Adipose Tissue/metabolism
• Down-Regulation
• Humans
• Insulin Resistance/genetics
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Obesity/genetics
• Obesity/metabolism
• Oxidoreductases/genetics
• Oxidoreductases/metabolism

• IL-6;
• Rheumatoid arthritis;
• TNFAIP3;
• TNFAIP9
• TNFα;

Six transmembrane protein of prostate 2 (STAMP2) is a protein that has been extensively studied due to its association with prostate cancer. Currently, STAMP2 is well known for its critical role in metabolism and modulating inflammatory signals. Even so, the molecular mechanism of STAMP2 activity and its downstream effectors are still largely unknown. Here, we review the current knowledge of STAMP2, and suggest possible explanations for some of its less well-understood features. A few studies suggest that STAMP2 may interact with mitochondria. Considering STAMP2 functions as a potential component of mitochondrial biology may yield valuable insight into this protein.

• STAMP2
• inflammation
• insulin resistance.
• metabolism
• metalloreductase
• mitochondria

• gene expression
• metabolic diseases
• lungs
• cholesterol
• particulate matter
• mouse

• Air Pollutants/adverse effects
• Air Pollutants/toxicity
• Animals
• Atherosclerosis/chemically induced
• Bronchoalveolar Lavage Fluid/chemistry
• Bronchoalveolar Lavage Fluid/cytology
• Gene Expression Regulation/drug effects
• Gene Expression Regulation/physiology
• Inflammation/chemically induced
• Interleukin-6/chemistry
• Interleukin-6/genetics
• Interleukin-6/metabolism
• Metabolic Syndrome/chemically induced
• Mice
• Particulate Matter/toxicity
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Saudi Arabia
• Tumor Necrosis Factor-alpha/chemistry
• Tumor Necrosis Factor-alpha/metabolism

• P30 CA016087 NCI NIH HHS
• P30 ES000260 NIEHS NIH HHS
• P30ES000260 NIEHS NIH HHS

Six transmembrane protein of prostate (Stamp) proteins play an important role in prostate cancer cell growth. Recently, we found that Stamp2 has a critical role in the integration of inflammatory and metabolic signals in adipose tissue where it is highly expressed and regulated by nutritional and metabolic cues. In this study, we show that all Stamp family members are differentially regulated during adipogenesis: whereas Stamp1 expression is significantly decreased upon differentiation, Stamp2 expression is increased. In contrast, Stamp3 expression is modestly changed in adipocytes compared to preadipocytes, and has a biphasic expression pattern during the course of differentiation. Suppression of Stamp1 or Stamp2 expression both led to inhibition of 3T3-L1 differentiation in concert with diminished expression of the key regulators of adipogenesis - CCAAT/enhancer binding protein alpha (C/ebpα) and peroxisome proliferator-activated receptor gamma (Pparγ). Upon Stamp1 knockdown, mitotic clonal expansion was also inhibited. In contrast, Stamp2 knockdown did not affect mitotic clonal expansion, but resulted in a marked decrease in superoxide production that is known to affect adipogenesis. These results suggest that Stamp1 and Stamp2 play critical roles in adipogenesis, but through different mechanisms.

• 3T3-L1 Cells
• Adipocytes/drug effects
• Adipocytes/metabolism
• Adipocytes/physiology
• Adipogenesis/drug effects
• Adipogenesis/genetics
• Animals
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/metabolism
• Cell Differentiation/drug effects
• Cell Differentiation/genetics
• Gene Expression Regulation/drug effects
• Gene Expression Regulation/physiology
• Gene Knockdown Techniques
• Membrane Proteins/antagonists & inhibitors
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mice
• Multigene Family/genetics
• RNA, Small Interfering/pharmacology

• Genetic association study
• Han Chinese
• Metabolic syndrome
• STAMP2

• Asian People/genetics
• Blood Glucose
• Blood Pressure
• Case-Control Studies
• China/epidemiology
• Coronary Artery Disease/epidemiology
• Coronary Artery Disease/etiology
• Coronary Artery Disease/genetics
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genetic Variation
• Haplotypes
• Humans
• Inflammation/epidemiology
• Inflammation/genetics
• Insulin Resistance/genetics
• Male
• Membrane Proteins/genetics
• Metabolic Syndrome/complications
• Metabolic Syndrome/epidemiology
• Metabolic Syndrome/genetics
• Middle Aged
• Oxidoreductases/genetics
• Phenotype
• Risk Factors
• Signal Transduction

• Adipocyte
• Copper Transport
• Cupric Reductase
• Ferric Reductase
• Insulin Resistance
• Iron
• Iron Metabolism
• Steap3
• Steap4
• X-ray Crystallography

Six transmembrane protein of prostate 2 (STAMP2) plays a key role in linking inflammatory and diet-derived signals to systemic metabolism. STAMP2 is induced by nutrients/feeding as well as by cytokines such as TNFα, IL-1β, and IL-6. Here, we demonstrated that STAMP2 protein physically interacts with and decreases the stability of hepatitis B virus X protein (HBx), thereby counteracting HBx-induced hepatic lipid accumulation and insulin resistance. STAMP2 suppressed the HBx-mediated transcription of lipogenic and adipogenic genes. Furthermore, STAMP2 prevented HBx-induced degradation of IRS1 protein, which mediates hepatic insulin signaling, as well as restored insulin-mediated inhibition of gluconeogenic enzyme expression, which are gluconeogenic genes. We also demonstrated reciprocal expression of HBx and STAMP2 in HBx transgenic mice. These results suggest that hepatic STAMP2 antagonizes HBx-mediated hepatocyte dysfunction, thereby protecting hepatocytes from HBV gene expression.

• Animals
• Apoptosis/physiology
• Arthritis/metabolism
• Interleukin-6/metabolism
• Macrophages, Peritoneal/pathology
• Male
• Membrane Proteins/deficiency
• NF-kappa B/metabolism
• STAT3 Transcription Factor/metabolism
• Signal Transduction/physiology

Histamine releasing factor (HRF), also known as translationally controlled tumor protein (TCTP), is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here, we will highlight the history of the molecule, its clinical implications with a focus on its extracellular functioning, and its potential role as a therapeutic target in asthma and allergy. The cells and cytokines produced when stimulated or primed by HRF/TCTP are detailed as well as the downstream signaling pathway that HRF/TCTP elicits. While it was originally thought that HRF/TCTP interacted with IgE, the finding that cells not binding IgE also respond to HRF/TCTP called this interaction into question. HRF/TCTP, or at least its mouse counterpart, appears to interact with some, but not all IgE and IgG molecules. HRF/TCTP has been shown to activate multiple human cells including basophils, eosinophils, T cells, and B cells. Since many of the cells activated by HRF/TCTP participate in the allergic response, extracellular functions of HRF/TCTP may exacerbate the allergic, inflammatory cascade. Particularly exciting is that small molecule agonists of Src homology 2-containing inositol phosphatase-1 have been shown to modulate the phosphoinositide 3-kinase/AKT pathway and may control inflammatory disorders. This review discusses this possibility in light of HRF/TCTP.

• human basophils
• human eosinophils
• inducible transgenic mouse
• interleukin 13
• interleukin 4
• translationally controlled tumor protein (TCTP)

• 3T3-L1 Cells
• Animals
• Biological Transport/physiology
• Caveolae/metabolism
• Caveolin 1
• Caveolins/metabolism
• Membrane Proteins/metabolism
• Mice
• Signal Transduction/physiology