Uroplakin II
Uroplakin III
Uroplakin Ib
Uroplakin Ia
Urinary Bladder
Tetraspanins
Membrane Proteins
Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. (1/45)
Although many genetic alterations are known to be associated with human transitional cell carcinoma (TCC) of the urinary bladder, relatively little is known about the roles of these molecular defects, singular or in combination, in bladder tumorigenesis. We have developed a transgenic mouse model of bladder tumorigenesis using a 3.6-kb promoter of uroplakin II gene to drive the urotheliums-specific expression of oncogenes. In this study, we demonstrate that transgenic mice bearing a low copy number of SV40T transgene developed bladder carcinoma in situ (CIS), whereas those bearing high copies developed CIS as well as invasive and metastatic TCCs. These results indicate that the SV40T inactivation of p53 and retinoblastoma gene products, defects frequently found in human bladder CIS and invasive TCCs, can cause the aggressive form of TCC. Our results also provide experimental proof that CIS is a precursor of invasive TCCs, thus supporting the concept of two distinct pathways of bladder tumorigenesis (papillary versus CIS/invasive TCC). This transgenic system can be used for the systematic dissection of the roles of individual or combinations of specific molecular events in bladder tumorigenesis. (+info)Immunohistochemical analysis of uroplakins, urothelial specific proteins, in ovarian Brenner tumors, normal tissues, and benign and neoplastic lesions of the female genital tract. (2/45)
Uroplakins are the characteristic integral membrane proteins in terminally differentiated, superficial urothelial asymmetric unit membrane. Brenner tumors of the ovary and Walthard cell nests of Fallopian tubes have been considered to represent urothelial differentiation in the female genital tract, but no definitive differentiation marker has been demonstrated supporting such a conclusion. An immunohistochemical analysis was performed to assess the expression of uroplakins in these lesions as well as in various benign and neoplastic lesions and normal tissues of the female genital tract. Focal expression of uroplakins was observed on the luminal surface of ovarian Brenner tumor cells forming microcysts in all 5 cases examined. In contrast, uroplakins were slightly expressed in only 1 of 12 cases of Walthard cell nests, even in the presence of microcyst formation. Uroplakins were not expressed in other benign or malignant lesions or normal tissues of the female genital tract. These results support the hypothesis that the Brenner tumor and possibly Walthard cell nests represent urothelial (transitional cell) differentiation. (+info)Comparison of uroplakin expression during urothelial carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in rats and mice. (3/45)
The expression of uroplakins, the tissue-specific and differentiation-dependent membrane proteins of the urothelium, was analyzed immunohistochemically in N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-treated rats and mice during bladder carcinogenesis. Male Fischer 344 rats were treated with 0.05% BBN in the drinking water for 10 wk and were euthanatized at week 20 of the experiment. BBN was administered to male B6D2F, mice; it was either provided at a rate of 0.05% in the drinking water (for 26 wk) or 5 mg BBN was administered by intragastric gavage twice weekly for 10 wk, followed by 20 wk without treatment. In rats, BBN-induced, noninvasive, low-grade, papillary, transitional cell carcinoma (TCC) showed decreased uroplakin-staining of cells lining the lumen but showed increased expression in some nonluminal cells. In mice, nonpapillary, high-grade dysplasia, carcinoma in situ, and invasive carcinoma were induced. There was a marked decrease in the number of uroplakin-positive cells lining the lumen and in nonluminal cells. This occurred in normal-appearing urothelium in BBN-treated mice and in dysplasic urothelium, in carcinoma in situ, and in invasive TCC. The percentage of uroplakin-positive nonluminal cells was higher in control mice than in rats, but it was lower in the mouse than in the rat after BBN treatment. Uroplakin expression was disorderly and focal in BBN-treated urothelium in both species. These results indicate that BBN treatment changed the expression of uroplakins during bladder carcinogenesis, with differences in rats and mice being related to degree of tumor differentiation. (+info)Detection of circulating cancer cells by reverse transcription-polymerase chain reaction for uroplakin II in peripheral blood of patients with urothelial cancer. (4/45)
Few attempts have been made at the molecular detection of urothelial cancer cells in the blood or lymph nodes mainly because of an absence of good candidate molecular or genetic changes specific to urothelial cancer or urothelium. In 1990, however, genes that encode urothelium-specific transmembrane proteins, uroplakins (UPs), were cloned. We have established a method of detecting circulating cancer cells in peripheral blood of patients with transitional cell carcinoma by nested reverse transcription-PCR assay for UP II. UP II mRNA-positive cells were detected in 3 (10.3%) of 29 patients with superficial cancers (pTa-1N0M0), 4 (28.6%) of 14 patients with muscularly invasive cancers (pT2-4N0M0), 2 (40.0%) of 5 loco-regional node-positive patients (pN1-2M0), and 6 (75.0%) of 8 patients with distant metastases. Positive rates, therefore, increased with tumor extension (P = 0.0033, Kruskal-Wallis test). Furthermore, sequential blood sampling was performed in three patients with metastases during and after systemic chemotherapy, and UP-II-positive cells were found to have disappeared in two patients who responded well to the systemic chemotherapy. These results suggest that our nested reverse transcription-PCR assay for UP II is highly specific and might be used as a tumor marker for molecular staging of urothelial cancers, although the sensitivity is not so optimal. (+info)Human uroplakin Ib in ocular surface epithelium. (5/45)
PURPOSE: To investigate the expression and localization of the human gene encoding uroplakin Ib in ocular surface epithelium. METHODS: The full-length cDNA of human uroplakin Ib was isolated from a cDNA library of human corneal epithelium, and the expression of uroplakin Ib in various tissues was examined by reverse transcription-polymerase chain reaction (RT-PCR). In cornea and conjunctiva, the expressions of uroplakin Ia, II, and III were also examined by RT-PCR. Finally, the localization of uroplakin Ib in the ocular surface was analyzed by immunofluorescence confocal microscopy, by using an antiserum against a synthetic peptide. RESULTS: Two mRNA isoforms, arising through two polyadenylation sites, were isolated. RT-PCR detected uroplakin Ib in cornea, conjunctiva, bladder, placenta, and kidney. Among other uroplakins, uroplakin II was also faintly detected in cornea and conjunctiva. Immunofluorescence confocal microscopy documented uroplakin Ib protein in the cell membranes of superficial and wing cells in the corneal epithelium. It was not found, however, in the most apical corneal epithelial cells. In limbus and conjunctiva, uroplakin Ib was also localized in the cell membranes of all epithelial layers, apart from the most apical cells. CONCLUSIONS: Uroplakin Ib is highly expressed in ocular surface epithelia. As in bladder epithelium, uroplakin Ib may protect the ocular surface from bacterial infection. (+info)Detection of epidermal growth factor receptor mRNA in peripheral blood: a new marker of circulating neoplastic cells in bladder cancer patients. (6/45)
Despite the large number of studies performed in solid tumors, few attempts at molecular detection of urothelial cells in blood have been made. Specifically, only uroplakin II (UP-II) and cytokeratin 20 (CK-20) have been suggested as tumor markers in the blood of bladder cancer patients. Epidermal growth factor receptor (EGFR) mRNA expression was found in the blood of patients with some types of carcinoma; nevertheless, its expression has been never investigated in the blood of patients with urothelial tumors. We used a EGFR-based reverse transcription-PCR assay for the detection of tumoral cells in the blood of 27 patients with bladder cancer, in 30 healthy donors, and in 9 patients with cystitis. EGFR expression was compared with that of known markers of circulating epithelial cells, CK-19 and CK-20, and to a urothelial-specific marker, UP-II. Analysis by reverse transcription-PCR and Southern blot hybridization showed no evidence of EGFR and UP-II mRNA expression in any of the samples used as controls. Analysis of healthy donors showed mRNA expression for CK-19 and CK-20 in 6 of 30 and in 4 of 30 samples, respectively. All patients with cystitis resulted negative for EGFR expression, whereas 3 of 9, 2 of 9, and 3 of 9 were found expressing CK-19, CK-20, and UP-II, respectively. Among blood samples from tumoral patients, 74% had EGFR mRNA and 41% had positive signals for CK-19, whereas positivity for CK-20 and UP-II was found in 15% and 37% of patients, respectively. These results seem to indicate that EGFR mRNA in the blood may be a useful tumor marker in bladder cancer patients, as well as in other patients with epithelial tumors. (+info)Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. (7/45)
Urothelial tumors develop along two distinctive phenotypic pathways (superficial papillary non-invasive tumors versus flat carcinoma in situ lesions), with markedly different biological behavior and prognosis. Although multiple genetic alterations have been identified in human bladder cancer, their cause-effect relationship with the two pathways has not been firmly established. Using a urothelium-specific promoter of the uroplakin II gene, we showed earlier in transgenic mice that the urothelial expression of SV40T antigen, which inactivates p53 and pRb, induced carcinoma in situ and invasive and metastatic bladder cancer. In striking contrast, we demonstrate here that the urothelial expression of an activated Ha-ras in transgenic mice caused urothelial hyperplasia and superficial papillary non-invasive bladder tumors. These results provide strong, direct experimental evidence that the two phenotypical pathways of bladder tumorigenesis are caused by distinctive genetic defects. Our results indicate that Ha-ras activation can induce urothelial proliferation in vivo; and that urothelial hyperplasia is a precursor of low-grade, superficial papillary bladder tumors. Our transgenic models provide unique opportunities to study the detailed molecular events underlying different types of bladder neoplasms, and can serve as useful preclinical models for evaluating the in vivo efficacy of preventive and therapeutic agents that act on various signaling pathways in bladder cancer. (+info)Molecular determination of perivesical and lymph node metastasis after radical cystectomy for urothelial carcinoma of the bladder. (8/45)
PURPOSE: Current methods used to determine the pathological stage of the primary tumor and associated lymphatics after radical cystectomy are tedious, costly, and may lack the sensitivity afforded by molecular approaches such as reverse transcription-PCR (RT-PCR) for markers specific for urothelial tissue such as the uroplakin II (UPII) gene. Thus, we sought to evaluate an objective and sensitive molecular approach for the assessment of perivesical extension and lymph node status after radical cystectomy, based on the detection of UPII expression using RT-PCR and compare this assay to standard clinical and pathological examination. EXPERIMENTAL DESIGN: From November 1999 to September 2000, 27 patients with clinical T(a)-T(3)N(0)M(0) urothelial bladder cancer underwent radical cystectomy, 19 (70%) of which also had pelvic lymphadenectomy. At the completion of cystectomy, systematic biopsies of the external surface of the bladder specimen as well as from the largest palpable lymph node found at lymphadenectomy were obtained for molecular analysis. RT-PCR analysis for UPII mRNA was carried out on these biopsy specimens, and results were compared with data obtained from conventional pathological examination. RESULTS: Pathologically organ-confined tumors had a 42% (5 of 12) incidence of positive signals in the perivesical tissues and 17% (1 of 7) in the lymph nodes. Corresponding percentages for pT(3a)N(0) and pT(3b)-T(4)N(0) lesions were 67% (4 of 6)/25% (1 of 4) and 67% (4 of 6)/33% (2 of 6), respectively. Overall, pathologically node-negative cancers had a perivesical positivity rate of 54% (13 of 24) and a lymph node positivity rate of 25% (4 of 16). All patients with pathologically positive nodes had positive UPII signals in the lymph node sample. CONCLUSIONS: This molecular assay aimed at assessing perivesical extension and lymph node status after radical cystectomy appears to identify patients that may harbor residual disease not appreciated by conventional histology. Larger studies with 5-7-year follow-up will be required to determine the prognostic significance of such molecular information. (+info)Uroplakin II is a type of protein that is a component of the urothelium, which is the tissue that lines the urinary tract. Specifically, uroplakins are part of the asymmetric unit membrane (AUM) of the urothelial plaques, which are specialized structures on the apical surface of the urothelium. These plaques help to provide a barrier function and protect the underlying tissues from various harmful substances in the urine. Uroplakin II is a transmembrane protein that forms heterodimers with other uroplakins, such as uroplakin Ib, to create the building blocks of the urothelial plaques.
Uroplakin III is a protein that is a component of urothelial plaques, which are specialized structures found on the surface of urothelial cells in the urinary bladder. Urothelial plaques play an important role in maintaining the barrier function and permeability properties of the urothelium.
Uroplakin III is a member of the uroplakin family of proteins, which includes UPIa, UPII, UPIII, and UPIIIA. These proteins are synthesized in the endoplasmic reticulum and transported to the Golgi apparatus, where they form heterodimers that are then transported to the plasma membrane. At the plasma membrane, the heterodimers assemble into larger complexes called urothelial plaques.
Uroplakin III is a transmembrane protein with a molecular weight of approximately 27 kDa. It has been shown to play a role in the formation and stability of urothelial plaques, as well as in the regulation of ion transport across the urothelium. Mutations in the gene encoding Uroplakin III have been associated with certain bladder diseases, including interstitial cystitis/bladder pain syndrome and bladder cancer.
Uroplakin Ib is not a recognized medical term or concept in and of itself. However, Uroplakins are a group of proteins found on the surface of urothelial cells, which make up the lining of the urinary tract. These proteins play an important role in maintaining the barrier function and integrity of the urothelium.
Uroplakin Ib is one of four major uroplakins (Ia, Ib, II, and III) that form complexes called uroplakins plaques on the apical surface of superficial urothelial cells. These plaques are thought to provide a protective barrier against urinary constituents, as well as contribute to the low permeability of the urothelium.
Therefore, while "Uroplakin Ib" may not have its own medical definition, it is an important component of the larger structure and function of uroplakins in the urinary tract.
Uroplakin Ia is not a medical term itself, but it is a component of uroplakins which are a group of proteins found in the urothelium, the tissue that lines the urinary tract. Uroplakins are involved in the formation of the asymmetric unit membrane (AUM) of the urothelial plaques, which are specialized structures on the apical surface of the superficial urothelial cells. These plaques provide a barrier function and protect the underlying tissues from various harmful substances in urine.
Uroplakin Ia is one of the four major uroplakins (UPIa, UPIb, UPII, and UPIII) that form heterodimers and then assemble into larger complexes to form the urothelial plaques. Specifically, Uroplakin Ia combines with Uroplakin Ib to form a heterodimer, which then associates with UPII and UPIII heterodimers to form a tetraspanin complex. These complexes are then incorporated into the AUM of the urothelial plaques.
Abnormalities in uroplakins have been associated with various urological disorders, including bladder cancer, interstitial cystitis, and chronic pelvic pain syndrome.
Urothelium is the specialized type of epithelial tissue that lines the urinary tract, including the renal pelvis, ureters, bladder, and urethra. It is a type of transitional epithelium that can change its shape and size depending on the degree of distension or stretching of the organs it lines.
The main function of urothelium is to provide a barrier against urine, which contains various waste products and potential irritants, while also allowing the exchange of ions and water. The urothelial cells are joined together by tight junctions that prevent the passage of substances through the paracellular space, and they also have the ability to transport ions and water through their cell membranes.
In addition to its barrier function, urothelium is also involved in sensory and immune functions. It contains specialized nerve endings that can detect mechanical and chemical stimuli, such as stretch or irritation, and it expresses various antimicrobial peptides and other defense mechanisms that help protect the urinary tract from infection.
Overall, urothelium plays a critical role in maintaining the health and function of the urinary tract, and its dysfunction has been implicated in various urinary tract disorders, such as interstitial cystitis/bladder pain syndrome and bladder cancer.
The urinary bladder is a muscular, hollow organ in the pelvis that stores urine before it is released from the body. It expands as it fills with urine and contracts when emptying. The typical adult bladder can hold between 400 to 600 milliliters of urine for about 2-5 hours before the urge to urinate occurs. The wall of the bladder contains several layers, including a mucous membrane, a layer of smooth muscle (detrusor muscle), and an outer fibrous adventitia. The muscles of the bladder neck and urethra remain contracted to prevent leakage of urine during filling, and they relax during voiding to allow the urine to flow out through the urethra.
Tetraspanins are a family of membrane proteins that are characterized by the presence of four transmembrane domains. They are widely expressed in various tissues and cells, where they play important roles in regulating cell development, activation, motility, and fusion. Tetraspanins can interact with other membrane proteins, such as integrins, receptors, and enzymes, to form complexes that function in signal transduction, trafficking, and adhesion. They also participate in the regulation of various cellular processes, including cell proliferation, differentiation, survival, and apoptosis. Some tetraspanins have been implicated in the pathogenesis of various diseases, such as cancer, autoimmune disorders, and viral infections.
Urinary Bladder Neoplasms are abnormal growths or tumors in the urinary bladder, which can be benign (non-cancerous) or malignant (cancerous). Malignant neoplasms can be further classified into various types of bladder cancer, such as urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma. These malignant tumors often invade surrounding tissues and organs, potentially spreading to other parts of the body (metastasis), which can lead to serious health consequences if not detected and treated promptly and effectively.
Membrane proteins are a type of protein that are embedded in the lipid bilayer of biological membranes, such as the plasma membrane of cells or the inner membrane of mitochondria. These proteins play crucial roles in various cellular processes, including:
1. Cell-cell recognition and signaling
2. Transport of molecules across the membrane (selective permeability)
3. Enzymatic reactions at the membrane surface
4. Energy transduction and conversion
5. Mechanosensation and signal transduction
Membrane proteins can be classified into two main categories: integral membrane proteins, which are permanently associated with the lipid bilayer, and peripheral membrane proteins, which are temporarily or loosely attached to the membrane surface. Integral membrane proteins can further be divided into three subcategories based on their topology:
1. Transmembrane proteins, which span the entire width of the lipid bilayer with one or more alpha-helices or beta-barrels.
2. Lipid-anchored proteins, which are covalently attached to lipids in the membrane via a glycosylphosphatidylinositol (GPI) anchor or other lipid modifications.
3. Monotopic proteins, which are partially embedded in the membrane and have one or more domains exposed to either side of the bilayer.
Membrane proteins are essential for maintaining cellular homeostasis and are targets for various therapeutic interventions, including drug development and gene therapy. However, their structural complexity and hydrophobicity make them challenging to study using traditional biochemical methods, requiring specialized techniques such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and single-particle cryo-electron microscopy (cryo-EM).
Uroplakins are a group of proteins found in the urothelium, which is the tissue that lines the urinary tract. These proteins are specifically located in the apical surface of the urothelial cells, where they form part of the asymmetric unit membrane (AUM) and play a crucial role in maintaining the barrier function of the urothelium. Uroplakins are organized into large complexes called uroplakin plaques, which cover approximately 70-80% of the apical surface of superficial urothelial cells. There are four major types of uroplakins, known as uroplakin Ia, Ib, II, and III, each with distinct structural and functional properties. Mutations in genes encoding uroplakins have been associated with certain bladder diseases, such as interstitial cystitis and bladder cancer.