{"title":"Epidermal differentiation and keratin gene expression.","authors":"E Fuchs","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Epidermal keratinocytes are ideal as a model system for the study of mammalian differentiation because primary cells have a high proliferative capacity and can be cultured under conditions enabling a balance of growth and differentiation. In addition, epidermal keratin genes have been cloned and characterized, and their strong promoters provide a means of high-level expression of transgenes in the epidermis of mice. For these reasons, considerable headway has been made in recent years in the quest to elucidate the biological pathways involved in the control of epidermal growth and differentiation. An understanding of these mechanisms is essential to realizing the potential of epidermal keratinocytes for drug delivery and gene therapy. This paper reviews what is presently known about epidermal growth and differentiation, with emphasis on the expression of epidermal-specific genes.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"290-302"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prevention of cancer metastasis in mice with fibronectin-related substances.","authors":"I Azuma, I Saiki","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Since the adhesive interaction between tumor cells and host cells, or extracellular matrix (ECM), presumably plays a crucial role in metastatic formation during a series of complex events, we used synthetic or recombinant polypeptide analogues, poly(RGD) or CH-271-based on Arg-Gly-Asp(RGD) sequence or functional domains in fibronectin. Use of these analogues regulated the mechanisms involved in cell adhesion during the metastatic process. Poly(RGD) effectively inhibited the experimental lung and liver metastasis when coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B-16-BL6 melanoma, multiple administrations of this polypeptide, before or after surgical excision of the primary tumor, resulted in significant inhibition of tumor metastasis without affecting the growth of the primary tumor. Further, it substantially prolonged the survival time of mice. The mechanism responsible for the inhibition of tumor metastasis by the polypeptides is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the cellular adhesive process of metastasis. The combination of CH-271 fusion polypeptide and anticancer drugs, i.e., anti-adhesion therapy and chemotherapy, caused a dramatic inhibition of lung and liver metastasis of tumors when compared with either treatment alone, or in the control. Since the polypeptides derived from cell adhesion molecules showed no short-term toxicity to the host, they may provide a promising approach for the control of cancer metastasis.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"125-41"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Sialomucin ligands for selectins: a new family of cell adhesion molecules.","authors":"L A Lasky","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The specific migration of various leukocyte subsets to areas undergoing pathogenic attack is one of the cornerstones of the immune system. Assorted adhesion molecules, chemokines, non-protein signalling molecules, and their respective receptors are utilized during this process. The combinatorial matrix formed by this diversity of agents determines the cell type that migrates to a given class of inflammatory site. The selectins are a family of adhesion molecules that elicit the rolling response that initiates the inflammatory cascade. Selectins contain a type C lectin domain at their N-termini which recognizes sialylated, fucosylated carbohydrate ligands of the sialyl Lewis X (sLex) type. Recently, it has been demonstrated that these carbohydrate ligands are presented by a new class of adhesion molecules that have mucin-like structure and have been termed the sialomucin adhesion family. The function of this new family of adhesion molecules is to act as a scaffold that presents selectin carbohydrate ligands in a clustered, tissue specific manner to allow for higher avidity interactions between leukocytes and endothelial cells during the inflammatory process. In this manner, the appropriate type of leukocyte rolls adjacent to an inflammatory site in a temporally correct manner. This review will focus on the molecular and cellular biology of the sialomucin adhesion family and will discuss the possible implications of these findings on the development of specific inhibitors of selectin function.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"81-90"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19943869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cell adhesion and tumor metastasis.","authors":"E Ruoslahti","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Integrins, among the various classes of cell adhesion receptors, are particularly associated with cell adhesion to extracellular matrices. They are heterodimeric transmembrane proteins with large ectodomains and short cytoplasmic tails. In many cases the sequence recognized by the integrins in the extracellular matrix proteins is the tripeptide Arg-Gly-Asp (RGD). Short synthetic peptides containing this sequence can inhibit tumor cell invasion in vitro and tumor dissemination in vivo. Because the alpha 5 beta 1 integrin appears to be the target of the peptides in many types of tumors, we have used phage display libraries to analyze the specificity of alpha 5 beta 1 and have isolated potent and specific inhibitors for this integrin. Increased expression of the alpha 5 beta 1 integrin, which is a fibronectin receptor, can also suppress cell migration and tumor cell invasion. We suggest this effect may be mediated through increased deposition of fibronectin matrix around the cells, because we found that the fibrillar matrix fibronectin suppresses tumor cell migration. There is increasing evidence that signals are elicited by the binding of integrins to their target proteins. This possibility has generated a great deal of interest in the cytoplasmic molecules that might mediate the integrin-associated signaling. At least two kinases, a novel tyrosine kinase, focal adhesion kinase (fak), and protein kinase C (PKC), are activated by integrin-mediated cell attachment. Moreover, a phosphorylated 190 kDa protein-associated with the alpha v beta 3 integrin has been found Anchorage dependence of cells and the migration-promoting activity of cell adhesion molecules are likely to depend on signal transduction through such molecules.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"99-105"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19943872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S D Demo, A Kikuchi, K G Peters, A M MacNicol, A J Muslin, L T Williams
{"title":"Signaling molecules that mediate the actions of FGF.","authors":"S D Demo, A Kikuchi, K G Peters, A M MacNicol, A J Muslin, L T Williams","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Signaling by fibroblast growth factor (FGF) is critical for cellular growth and differentiation. We have studied the role of FGF and its receptor in development and also the signaling pathways utilized by these molecules. Transgenic mice expressing a dominant negative FGF receptor specifically in lung tissue fail to develop lungs. These findings suggest that FGF signaling is important for airway branching and alveolar formation. In Xenopus embryos, FGF is involved in the development of posterior structures. Induction of mesoderm by FGF is mediated by the serine-threonine kinase RAF. The expression of a dominant negative RAF selectively blocks the mesoderm-inducing action of FGF. Expression of activated RAF accentuated the development of posterior structures Other intracellular molecules that are involved with FGF signaling include RAS, a low-molecular weight GTP-binding protein. We have identified a novel gene (RIP, for RAS-interacting protein) that contains a RAS-binding domain. This domain is found in at least one other protein, ralGDS. Both RIP and ralGDS bind to activated RAS suggesting that these proteins are likely candidates for mediators of RAS function. These findings help elucidate the role of FGF signaling in development.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"243-9"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Matrix-degrading metalloproteinases in tumor progression.","authors":"L M Matrisian, J Wright, K Newell, J P Witty","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The matrix-degrading metalloproteinases (MMPs) have been implicated in tumor invasion and metastasis. Recently it has become clear that the expression of MMPs in tumors is frequently localized to stromal cells surrounding malignant tumor cells. In the mouse skin model of multi-stage carcinogenesis, the MMP stromelysin is expressed in stromal fibroblast-like cells surrounding benign and malignant squamous cell carcinomas. Conversion of these tumors to highly invasive and metastatic spindle-cell tumors is however, associated with the expression of stromelysin-1 mRNA in the tumor cells themselves. The analysis of MMPs in human colon adenocarcinomas at different stages of tumor progression revealed that matrilysin was the only MMP expressed in the tumor cells, while stromelysin-1 and stromelysin-3 mRNA was detected in stromal cells surrounding malignant tumor cells. Matrilysin mRNA is detected in benign tumors as well as malignant tumor cells, and the relative level and percent of tumors expressing matrilysin correlates with the stage of tumor progression. These results suggest that both stromal and tumor cell metalloproteinases may contribute to tumor invasion and metastasis, and also suggests that MMPs may play a role in earlier events in the tumor progression pathway. A potential role for MMPs in tumor growth is illustrated by results which suggest that the expression of matrilysin in human colon cancer-derived cells increases tumorigenicity following injection into the cecum, and that transgenic mice expressing matrilysin mRNA show a marked proliferative response. MMPs may therefore play multiple roles in tumor progression.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"152-61"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular and cellular basis for cell to cell interaction: its significance in cancer. Proceedings of the 24th International Symposium of the Princess Takamatsu Cancer Research Fund. Tokyo, Japan.","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"1-357"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20109984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S Aizawa, T Yagi, Y Furuta, Y Ikawa, S Nada, H Nakagawa, M Okada
{"title":"Non-receptor tyrosine kinases in mammalian neurogenesis.","authors":"S Aizawa, T Yagi, Y Furuta, Y Ikawa, S Nada, H Nakagawa, M Okada","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Several members of the Src family of non-receptor tyrosine kinases are expressed at high levels in embryonic neural tissues as well as in adult brain. Relatively little has been known, however, about their roles in neural development. Attempts to clarify this by production of mutant mice have been unsuccessful because of gene redundancy. We earlier isolated a new cytoplasmic protein tyrosine kinase, Csk, and showed that it inactivates uniquely all members of non-receptor tyrosine kinases in vitro. Here, we have generated Csk-deficient mouse embryos and shown that Csk is indeed an indispensable negative regulator for all non-receptor tyrosine kinases in vivo, and that regulated activity of these kinases is essential for normal development of mice at the neural stage. The signaling pathway through Src-family kinases during neurulation is also discussed.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"323-37"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19944249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular aspects of the loss of cell adhesion and gain of invasiveness in carcinomas.","authors":"W Birchmeier","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>It has been realized that the loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumor cells, is often a consequence of reduced intercellular adhesion. A variety of recent reports have indicated that the primary cause for the 'scattering' of the cells in invasive carcinomas is a disturbance of the integrity of intercellular junctions. It has also been suggested that during invasion, carcinoma cells convert to a sort of mesenchymal stage, as do normal epithelial cells during development. This paper discusses permanent and transient molecular mechanisms which lead to the impairment of junction integrity of epithelial cells and thus to the progression of carcinomas towards a more invasive state.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"214-32"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R Derynck, R H Chen, R Ebner, E H Filvaroff, S Lawler
{"title":"An emerging complexity of receptors for transforming growth factor-beta.","authors":"R Derynck, R H Chen, R Ebner, E H Filvaroff, S Lawler","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Transforming growth factor-beta (TGF-beta) is a multifunctional protein that modulates cell proliferation and interaction with the extracellular matrix. Three common TGF-beta receptors are found on the cell surface. The type III receptor is a transmembrane proteoglycan with a short cytoplasmic domain and is thought not to be involved in TGF-beta induced signalling. In contrast, the type II and type I receptors are transmembrane serine/threonine kinases. The type II receptor determines the ligand specificity, whereas the type I receptor interacts with the type II receptor and may not have a ligand binding specificity by itself. Both type II and type I receptors are involved in TGF-beta induced signalling. The type II receptor, likely in conjunction with the type I receptor, is required for the antiproliferative effect of TGF-beta, whereas the type I receptor is the likely mediator of the effects of TGF-beta on the expression of several genes including some extracellular matrix proteins. To address the role of TGF-beta signalling in myoblast differentiation, we transfected a dominant negative mutant of the type II receptor in myoblasts, thus inhibiting type II receptor mediated signalling. These cells not longer had the ability to differentiate in vitro or in vivo, suggesting that TGF-beta signalling through the type II receptor provides competence for myoblastic differentiation. These studies also indicate that there are several signalling pathways involved in myoblastic differentiation, one of which is modulated by the TGF-beta signalling.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"264-75"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}