From a subtractive cDNA library» we isolated several cDNA clones which showed differential expression between highly and lowly metastatic human melanoma cell lines. One clone, desig nated nmb, showed preferential expression in the low-metastatic cell lines and was chosen for further characterization. Sequence analysis revealed that this clone represents a novel gene, encoding a putative transmembrane glycoprotein which showed the highest homology to the precursor of pMELI7, a melanocyte-specific protein. nmf> RNA expression was absent in most tumor-cell lines tested and not restricted to the melanocytic lineage. Transfection of a partial nmb cDNA into a highly metastatic melanoma cell line (BLM) resulted, in 2 of 3 transfectants, in slower subcutaneous tumor growth and, in I of 3 transfectants, in reduction of the potential for spontaneous metastasis in nude mice.
Expression of activated leukocyte cell adhesion molecule (ALCAM)/CD166 correlates with the aggregation and metastatic capacity of human melanoma cell lines (Am J Pathol 1998, 152:805-813). Immunohistochemistry on a series of human melanocytic lesions reveals that ALCAM expression correlates with melanoma progression. Most nevi (34/38) and all thin melanomas studied (Clark levels I and II) did not express ALCAM. In contrast, immunoreactivity was detected in the invasive, vertical growth phase of 2 of the 13 Clark level III lesions tested. The fraction of positive lesions further increased in Clark level IV (13/19) and in Clark level V (4/4) lesions. ALCAM expression was exclusively detectable in the vertical growth phase of the primary tumor. In melanoma metastases, approximately half of the lesions tested (13/28) were ALCAM positive. According to the Breslow-thickness, ALCAM expression was observed in less than 10% of the lesions that were thinner than 1.5 mm and in over 70% of the lesions that were thicker than 1.5 mm. Our results strongly suggest that ALCAM plays an important role in melanocytic tumor progression and depict it as a new molecular marker for neoplastic progression of primary human melanoma.
Activated leukocyte cell adhesion molecule (ALCAM/ CD166), a member of the immunoglobulin superfamily with five extracellular immunoglobulin-like domains, facilitates heterophilic (ALCAM-CD6) and homophilic (ALCAM-ALCAM) cell-cell interactions. While expressed in a wide variety of tissues and cells, ALCAM is restricted to subsets of cells usually involved in dynamic growth and/or migration processes. A structure-function analysis, using two monoclonal anti-ALCAM antibodies and a series of amino-terminally deleted ALCAM constructs, revealed that homophilic cell adhesion depended on ligand binding mediated by the membranedistal amino-terminal immunoglobulin domain and on avidity controlled by ALCAM clustering at the cell surface involving membrane-proximal immunoglobulin domains. Co-expression of a transmembrane ALCAM deletion mutant, which lacks the ligand binding domain, and endogenous wild-type ALCAM inhibited homophilic cell-cell interactions by interference with ALCAM avidity, while homophilic, soluble ligand binding remained unaltered. The extracellular structures of ALCAM thus provide two structurally and functionally distinguishable modules, one involved in ligand binding and the other in avidity. Functionality of both modules is required for stable homophilic ALCAM-ALCAM cell-cell adhesion.Adhesion molecules play an important role in development, leukocyte function, and homeostasis in multicellular organisms, which are mainly governed by inter-and intracellular communication via cell-cell interactions. Alterations in cellular adhesion and communication can contribute to uncontrolled cell growth (1) and life-threatening syndromes like leukocyte adhesion deficiency (2). Activation of adhesion molecules generally involves both modulation of affinity and avidity. The affinity of adhesion molecules often reflects a specific conformation of the extracellular ligand-binding domain. Avidity modulation involves changes in the cell surface distribution of adhesion molecules (e.g. lateral oligomerization), which leads to clusters of molecules and thereby specifically increases the number of available receptors at the site of cell-cell interaction.Activated leukocyte cell adhesion molecule (ALCAM/MEMD/ CD166) 1 is a type I transmembrane protein and a member of the Ig superfamily. It has over 90% homology with the chicken adhesion molecule BEN/SC1/DM-GRASP (3-5), and it has 30% identity and 50% similarity with the human melanoma cell adhesion molecule Mel-CAM/MUC18/CD146 (6). Furthermore, ALCAM has 93% sequence identity with the candidate liver high density lipoprotein receptor HB2 (7). ALCAM is involved in various physiological processes including hematopoiesis (8, 9), thymus development (10), the immune response (11), neurite extension (12), neural cell migration (13), and osteogenesis (14).ALCAM has a short cytoplasmic tail and its extracellular part comprises five Ig domains: two amino-terminal variable (V) type Ig domains followed by three constant (C) type Ig domains (V 1 V 2 C 1 C 2 C 3 ). ALCAM was first ident...
Recently we described that genetic sequences in the immediately upstream region of the c‐fes/fps proto‐oncogene, designated fur, constituted a transcription unit for a 4.5‐kb mRNA. Here we present characteristics of the genetic organization of fur and some features of its putative translation product which we call furin. The nucleotide sequence of a 3.1‐kbp fur‐specific cDNA isolated from a human cDNA library revealed an open reading frame of 1,498 bp from which the 499 carboxy‐terminal amino acids of the primary fur translational product could be deduced. Computer analysis indicated that furin contained a possible transmembrane domain which resembled that of class II MHC antigens. Furthermore, a cysteine‐rich region was present. Significant homology, especially with respect to the topography of cysteine residues, was found between the cysteine‐rich regions of the human insulin receptor, the human epidermal growth factor receptor and furin. From the data presented here we deduce that fur may encode a membrane‐associated protein with a recognition function.
The recently discovered fur gene encodes a membrane-associated protein with a recognition function. To further characterize the gene, we studied its expression by Northern blot analysis using poly(A)-selected RNA from a variety of organs of African green monkey and rat. The fur gene appeared to be differentially expressed, relatively high levels of fur mRNA being present in specimens of liver and kidney, low levels in brain, spleen, and thymus, and very low levels in heart muscle, lung, and testis. mRNA levels in specimens of human lung tissue without neoplastic lesions were also very low. Similar analyses of primary human lung carcinomas of different histopathological types revealed a highly selective and strong elevation offir expression in nonsmall cell lung carcinomas, but not in small cell lung carcinomas. These results indicate that fir expression can be used to discriminate between these two types of human lung cancer.
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