Abstract. CD44 is a ubiquitous surface molecule that exists as a number of isoforms, generated by alternative splicing of 10 "variant" exons. Little is known about the expression and function of the variant isoforms, except that certain isoforms may play a role in cancer metastasis. We produced mAbs against CD44 variant regions encoded by exons 4v, 6v, and 9v, by immunizing mice with a fusion protein spanning variant exons 3v to 10v. A comprehensive analysis of human tissues revealed that CD44 variant isoforms were expressed widely throughout the body, principally by epithelial cells. However there was differential expression of CD44 variant exons by different epithelia. Most epithelia expressed exon 9v, but much fewer expressed 6v or 4v. The regions of epithelia that expressed the highest levels of the variant isoforms were the generative cells, particularly the basal cells of stratified squamous epithelium, and of glandular epithelium. CD44 variant isoforms were also expressed differentially by leukocytes, with CD44-9v expressed at very low levels and CD44-6v and 4v virtually absent. However, CIM4-9v and CD44-6v were the main variants that were transiently upregulated on T cells after mitogenic stimulation and on myelomonocytic cell lines by TNFot and IFN~ treatment. Some epithelial cell lines could preferentially upregulate CIM4-6v upon IFN3, incubation. These results show that CD44 variant isoforms are expressed much more widely than first appreciated, and that expression of the variant isoforms on some cell types can be modulated by particular cytokines.C D44 is a widely expressed cell surface glycoprotein that serves as an adhesion molecule in cell-substrate and cell-cell interactions, including lymphocyte homing, hemopoiesis, cell migration, and metastasis (for reviews see Haynes et al., 1991; Underhill, 1992; Gtinthert, 1993;Lesley et al., 1993). CD44 also has other functions that relate to lymphocyte activation (Haynes et al., 1989) and the binding of certain cytokines to endothelium (Tanaka et al., 1993). CD44 is a proteoglycan with an NH2-terminal region that is structurally related to several hyaluronate binding proteins (Underhill, 1992). CD44 is known to bind hyaluronate and collagen (Carter and Wayner, 1988;Aruffo et al., 1990;Culty et al., 1990;Miyake et al., 1990) and a chondroitin sulfated form of CD44 binds fibronectin (Jalkanen and Jalkanen, 1992). Additional ligands for CD44 may well exist. The numerous functions and molecular interactions of CD44 probably relate to its complex structure. In addition to the "standard" 85-95-kD form (CD44s), severalThe Basel Institute for Immunology was founded and is supported by E Hoffman-La Roche Ltd., Basel, Switzerland.Address all correspondence to Dr. Charles R. Mackay, Leukosite Inc., 800 Huntington Ave., Boston, MA 02115, or Dr. Ursula Giinthert, The Basel Institute for Immunology, Grenzaeherstrasse 487, CH-4005 Basel, Switzerland.larger "variant" isoforms exist (CD44v) t that are generated by alternative splicing of at least 10 exons (Screaton et al....
CD44 is a transmembrane glycoprotein, which can exist in a multitude of isoforms due to alternative splicing of the pre-mRNA. We have generated monoclonal antibodies to several of these variant regions, which are encoded by 10 additional exons in the extracellular part of the molecule. CD44 variant isoforms have been reported to be involved in the malignant progression of rat and human tumours. The precise localization of CD44 variant isoforms in normal developmental and morphogenetic processes is essential for diagnostic studies of human tumorigenesis. Therefore, we have analysed a large number of different human tissues by immunohistochemistry for the expression of CD44 isoforms containing either exons 4v, 6v or 9v. Expression of exon 9v-isoforms was detected in almost all epithelia analysed, with a few exceptions. Exon 6v isoforms are expressed only in squamous and glandular epithelial, e.g. skin epidermis, sweat and sebaceous glands, oesophagus, ducts of the mammary gland, salivary and prostate glands. Detection of exon 4v-encoded isoforms was restricted to the epidermis and the oesophagus. Similar tissue distributions of CD44 variant isoforms were observed in 10-week-old fetal tissues. Since one of the ligands of CD44 is hyaluronic acid (HA), we also analysed the tissue distribution of HA synthetase. HA synthetase was detected in all tissues analysed, showing good correlation with the expression of the standard form of CD44, CD44s.
Alpha 6 integrin is an adhesion molecule that connects cells with extracellular matrix molecules of the laminin family. The laminin interaction seems to be essential for cell differentiation during embryogenesis and for the subsequent maintenance of tissue integrity in the adult. Alpha 6 integrin can also interact with laminin-independent cellular ligands and in this way plays a role in homing of leucocytes. Furthermore, in cancer biology alpha 6 integrin has an important role in metastasis and as a possible new prognostic factor; exact knowledge of alpha 6 integrin distribution in normal human tissues is therefore a crucial element. By immuno-histochemical methods we have screened alpha 6 integrin expression of representative human tissues from the adult and the embryonic organism. All tested epithelia were alpha 6 integrin positive, except for the endocrine cells of the pancreas and the adrenal glands. Heterogeneous staining was found on non-epithelial tissues. Strong staining was evident in peripheral nerves (Schwann cells), germ and Sertoli cells, endothelia, and smooth muscle cells of the myometrium. Weak staining was found in nerve cells of the stratum granulosum, the microglia, Kupffer's cells and stromal cells of the ovary. All fibroblasts, striated muscle cells and astrocytes were negative. The tissue distribution of alpha 6 integrin and the semi-quantitative estimation of their expression level should provide a better understanding of alpha 6 integrin function under normal and pathological conditions, in particular in tumour progression.
Zusammenfassung:Organisationsberatung und Organisationsentwicklung sollen die Leistungsfähigkeit der Kundenorganisation erhöhen -dieses offizielle, vertraglich vereinbarte Ziel wird jedoch häufig durch nicht offen kommunizierte hidden agendas konterkarikiert. Beratung kann durch das Kundensystem instrumentalisiert werden, z.B. um die Legitimität des eigenen ManagementHandelns nach außen hin nachzuweisen, um das Scheitern organisationaler Veränderungspro-zesse extern attribuieren zu können, um die Position des Auftraggebers in internen Machtkämpfen zu stärken oder um das System von Konflikten zu entlasten. Auf Beraterseite kön-nen der offizielle Professionalitätsanspruch mit der Notwendigkeit der Generierung von Folgeaufträgen und dem Interesse an der Vermarktung von Standardprodukten in Konkurrenz stehen. Im vorliegenden Beitrag werden Deutungsmöglichkeiten für solche hidden agendas diskutiert und mit Fallbeispielen aus der Praxis der Autoren illustriert. Abstract:Consulting and organization development claim to boost the client organization's efficiencythis official goal is frequently foiled by hidden agendas which are not officially communicated. Hidden functions of consulting are to prove to the management's legitimacy, to explain the failure of change processes, to strengthen the initator's position in internal power struggles or to relieve the system from conflict. On the consultants' side there is a tension between professionalism on one side and the necessity to secure follow-up projects and to sell standard products on the other side. The authors present possible interpretations for such hidden agendas and illustrate them with case studies from their practical experience as consultants.
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