摘要:

AbstractRetinoids, cytokines as well as 1,25‐dihydroxyvitamin D3[1,25(OH)2D3] and analogs possess properties known to contribute potentially to cancer chemopreventive and chemotherapeutic effects. They induce cell differentiation, inhibit cell prolifeation, suppress expression of viral oncogenes, and inhibit angiogenesis nexessary for tumor growth. Since clinical combination chemotherapy of cytotoxic agents has proven superior to monotherapy, This moddality might also be useful for other classes of antitumor drugs. A series of retinoids, such as all‐trans‐, 13‐cis‐, 9‐cis retinoic acid, and acitreti, cytokines, 1,25(OH)2D3, and analogs have been investigated in mocdel systems of defferentiation, proliferation, viral oncogenes, and angiogenesis. The three classes of compounds have common effects but nevertheless show a variance depending on the particular representative of each class. Combination of compounds of the different classes led in the various models to a hegher efficacy compared with the compounds given alone. Cytokines such as IFNα, IFNγ, G‐CSF, TNFα, IL‐1, and IL‐4 markedly potentiate the differentiation‐inducing effect of retinoids. Cytokines as well as retinoids combined with 1,25(OH)2D3and analogs synergistically enhanced differentiation induction in human transformed hemopoietic cell lines. On a series of human transformed epithelial cell lines a panel of cytokies, such as IFNα, IFNβ, TNFα, TGFβ, and EGF acted synergistically with retinoies on inhibition of proliferation. This was also observed by combining retinoids with 1,25(OH)2D3and analogs. Retinoids as well as interferons α and γ have the capacity to suppress the capacity to supperess the oncogene expression of human papilloma viruses which are involved in induction and growth of certain malignancies such as cervical cancer. All‐trans‐, 13‐cis‐, 9‐cis retinoic acid, and acitretin as well as IFNα inhinited the formation of newly formed blood vessels induced by injection of HPV harboring, tumorigenic cell lines into Balb/C mice. The combination of retinoids with IFNα was more efficacious in inhibition angiogenesis than a retinoid or IFNα given alone. Since there is evidence that cell differentiationl, cell proliferation, viral oncogene expression as well as angiogenesis play a role in tumor induction and/or progression of tumor growth, retinoids, cytokines, as well as 1,25(OH)2D3and analogs may be useful in chemoprevention and chemotherapy of neoplasms. based on the superior effect of combinations compared with administration of single compounds of these three classes under experimental conditions there is hope that also clinical application of combination treatment might bring as a step forward in chemopreventio and chemotherapy of cancer. This has already been proven in a very limited number o

ISSN:0730-2312    

DOI:10.1002/jcb.240560402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA diverse array of molecules involved in signal transduction have recently been recognised as containing a new homology domain, the pleckstrin homology (PH) domain. These include kinases (both serine/threonine and tyrosine specific), all currently known mammalian phospholipase Cs, GTPases, GTPage‐activatng proteins, GTpace‐exchange factors, “adapter” proteins, cyotskeletal proteins, and kinase substrates. This has sparked a new surge of research into elucidating its sturcture and function. The NMR solution structure of the PH domains of β‐spectrin and pleckstrin (the N‐terminal domain) both display a core consisting of seven anti‐parallel β‐sheet strands. The carboxy terminus is folded into a long α‐helix. The molecule is electrostatically polarised and contains a pocket which may be involved in the inding of a ligand. The PH domain overall topological relatedness to the retinoid inding protein family of molecules would suggest a lipid ligand could bind to this pocket. the prime function of the PH domain still remains to be elucidated. However, it has been shown to be important in signal transduction, most probably by mediating protein‐protein interactions. An extended PH domain of the β‐adrenergic receptor kinase (βARK), as well as that of several other molecules, can bind to βγ subunits of the heterotrimeric G‐proteins. The possibility that the PH domain, which is found in so many signalling molecules, being generally inovolved in βγ binding site appear to be concomitant in βARK, detailed analysis indicates that the PH domain is not generally a βγ binding domain. Thus, the race is on to find the ligands of each PH domain and determine a

ISSN:0730-2312    

DOI:10.1002/jcb.240560403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractHyperplastic lesions of the oral mucosa such as leukoplakia and oral lichan planus can eventually develop into squamous cell carcinomas. In the clinical treatment of these lesions it would be very important tobe able to predict the biological behaviour of an individual lesion. In 64 hyperplastic lesions and 85 squamous cell carcinomas of the oral mucosa, the expression of the mutant tumor suppressor gene p53and the grade of dysplasia of the lesions.

ISSN:0730-2312    

DOI:10.1002/jcb.240560404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA series of 16 experiments, using a total of 2,000 BD6rats, was designed in order to assess the ability of 8 individual agents or their combinations to modulate the liver and oesophageal carcinogenesis induced by multiple doses of diethylnitrosamine (DEN). Of the antioxidants tested, sodium selenite, ascorbic acid, and butylated hydroxytoluence generally exhibited protective effects on both types of tumors. In contrast, retinoic acid behaved as a promoter of DEN hepatocarcinogenesis, but this effect could be eliminated by its combination with either selenite or butylated hydroxytoluene. Caffeine and theophyline, when individually assayed, were devoid of significant protective effects, and the later methylxanthine stimulated oesophageal tumorigenesis when administered afer exposure to the carcinogen. Caffeine tended to decrease tje multiplicityof tumors and potentiated the inhibitory effect of selenite in the liver. Irrespective of combination with caffeine, treatment with phwnobarbital before each DEN injection tended to reduce the multiplicity of both liver and oesophageal tumors. On the other hand, the metabolic inhibitoe diethyldithiocarbamate, given after each DEN injection, dramatically enhancedd the incidence and multiplicity of oesophageal tumors. Thus, on the whole, modulation of DEN carcinogenesis varied depending on test agents, their conbinations, dosages, treatment schedules, and target organ.

ISSN:0730-2312    

DOI:10.1002/jcb.240560405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractWe have previously reported that the hyaluronan (HA) receptor RHAMM (Receptor for Mediated Motility) [Turley et al., 1991] and that HA stimulation of the motility of ras‐transformed fibroblasts is mediated via its interaction with RHAMM. Here we show that RHAMM also contains binding sites for heparin (HP) anbd that interaction of HP with these sites can regulates the locomotion ofras‐transformed fibroblasts. At low concentrations (0.01 mg/ml), HP inhibited HA‐induced locomotion ofras‐transformed cells in a manner independent of RHAMM. At higher, but still physioligical concentrations (0.1 mg/ml), HP alone stimulated cell locomotion and this stimulation appeared to be RHAMM‐dependent as it was blocked by anti‐RHAMM antibodies. Other related glycosaminogolycans such as chondroitin sulfate and dermatin sulfate had no effect on cell motility. In ligand blotting assays, GST‐RHAMM fusion protein was shown to bind biotin‐labelled HP and this binding was displaceable with unabelled HP. In similar lignad binding analyses conducted with truncations of RHAMM fusion protein, the binding region was found to be localizeed in the same 35 amino acid segment of RHAMM that contains the two HA binding domains. Synthetic peptides corresponding to these HA binding domains were retained on and bound effectively to an HP‐Sepharose affinity column. Fusion protein generated by linkage of these peptides to the non‐HP binding amino terminus of RHAMM conferred HP binding capacity to the genetically engineered proteins. Conversely, deletion of the HA binding domains of RHAMM resulted in fusion proteins devoid of HP binding activity. The relative affinities of RHAMM for HA and HP, as determined by competition and transblot assays as well as quantification of binding at various salt concentrations, indicated that RHAMM had lower affinity for HP than that for HA. These results demonstrate the existence of new HP binding motif that has biological rele

ISSN:0730-2312    

DOI:10.1002/jcb.240560406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe early growth response gene, Egr‐1, is up‐regulated transiently by mitogens and many other simuli in all cells tested. Using NIH3T3 cells conditionally expressing v‐sisfrom a metallothionein promoter, we show that the addition of Zn2+stimulates the production of PDGF‐B(v‐sis) and elicits the expression of Egr‐1 in a dose‐dependent and time‐regulated manner. The signal is likely independent of protein kinase C, but depends on tyrosine kinase and other kinase activities and is mediated by c‐Ha‐Ras since the presence of dominant‐negative mutants of Ras and Raf abrogates the induction of Egr‐1 expression by Zn2+. Transiently activated Ras expression in NIH3T3 cells also stimulates the transient expression of Egr‐1, but cells that constitutively express Rass do not have elevated levels of Egr‐1. Transient assays also demonstrated that Zn2+or activated Ras expression stimulated the activity of a 950 bp Egr‐1 promoter‐reporter gene construct and this is abrogated in the presence of mutant Ras and Raf. The accumulated data show that Egr‐1 gene expression is regulated by multiple mechanisms, as would be needed for putative role in Cell proliferation, in suppression of tran

ISSN:0730-2312    

DOI:10.1002/jcb.240560407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe bioactive lipid lysohosphatidic acid is besides a strong mitogen for quiescent fibroblasts, a potent inducer of phenotypic transformation on normal rat kidney cells. The lysophosphatidic acid induced loss of densityarrest is strongly inhibited by bradykinin. Although their effects on normal rat kidney cell proliferation are opposite, bradykinin mimics many of the intracellular effects induced upon lysophosphatidic acid receptor activation, including phosphoinositide turnover, Ca2+‐mobilization and arachidonic acid release. Bradykinin does not counteract the lysophosphatidic acid induced reduction of cAMP levels in normal rat kidney cells. However, bradykinin inhibits the lysophosphatidic acid and other growth factor induced phenotypic transformation through the induction of a so far uncharacterized prostaglandin G/H synthase product. The growth inhibitory effect of bradykinin is limited to density‐arrested cells, while upon prolonged treatment bradykinin itself is capable to induce the loss of densitydependent growth control. It is concluded that bradykinin is a bifunctional regulator of normal rat kindney cell proliferation and that its inhibitory effects are midiated via induction of a prostaglandin dervat

ISSN:0730-2312    

DOI:10.1002/jcb.240560408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe synthesis of type 1 colagen in bone cells is inhibited by the calcium‐regulating hormone 1,25‐dihydroxyvitamin D3. Earlier work from our laboratoties has indicated that vitamin D regulation is at the level of transcription, based on result from both nuclear run‐off assays and functional analysis of a hybrid gene consisting of a 3.6 kb COL1A1 promoter fragment fused to the chloraphenicol acetyltransferase reporter gene. In the present study, we investigated the molecular basis for vitamin D‐mediated transcriptional repression of the COL1A1 gene and report the identification of a region within the COL1A1 upstream promoter (the Hindlll‐Pstl restriction fragment between nucleotides‐2295 and ‐1670) which is necessary for 1,25‐dihydroxyvitamin D3responsiveness in osteoblastic cells. This hormone‐mediated inhibitory effect on the marker gene parallels the inhibition of the endogenous collagen gene. A 41 bp fragment from this region (between nucleotides‐2256 and ‐2216) contains a sequence which is very similar to vitamin D‐responsive elements identified in the osteocalcin gene. Estracts that binds specifically to this 41 bp fragment, as demonstrated by bandshift anslysis. However, deletion of this vitamin D receptor binding region from either a‐3.5 kb or a‐2.3 kb promoter fragment did not abolish vitamin D responsiveness. These results indicate that a vitamin D response element similar to that described for other D responsive genes (osteocalcin and osteopontin) does not alone mediate the repression of COL1A1

ISSN:0730-2312    

DOI:10.1002/jcb.240560409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractCell metabolism and function are modulated in part by cell and nuclear shape. Nuclear shape is controlled by the nuclear matrix, the RNA‐protein skeleton the nucleus, and its interactions with cytoskeletal systems such as intermediate filaments and actin microfilaments. The nuclear matrix plays an important role in cell function and gene expression because active genes are bound to the nuclear matrix whereas inactive genes are not. It is unknown, however, how genes move on and off the matrix, and whether these events require compositional protein changes, i.e., alterations in protein content of the nuclear matrix, or other, more subtle alterations and/or modificatins. The purpose of this investigation was to begin to determine how nuclear matrix protein composition is related to gene expression. We demonstrate that gene expression can change without apparent changes in the protein composition of the nuclear matrix in MCF10A breast epithelial cell

ISSN:0730-2312    

DOI:10.1002/jcb.240560410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe Steroid hormon 1α, @5‐Dihydroxyvitamin D3has been shown to expert rapid effect (15 s to 5 min) in osteoblast. These occur in osteoblast‐like cells lacking the nuclear vitamin D receptor, ROS 24/1, suggesting that a separate signalling system mediates the rapid action. These non‐genomic action include rapid activation of phospholipase C and opening of calcium channels, pointing to a membrane localization of this signalling system. Previous studies have shown that the 1β epimer of 1α25‐dihydroxyvitamina D3can block these rapid action, indicating that the 1β epimer may bind to the recptor responsible for the rapid action sin a competative manner. We have assessed the displacement of3H‐1α,25dihydroxyvitamin D3by vitamin D compounds, as well as the apparent dissociation constant of 1α25‐dihydroxyvitamin D3and its 1β epimer for the memberane receptor in membrane prepration from ROS 24/1 cells. Increasing concentrations of 1α25‐dihydroxyvitamin D3, 7.25 nM to 725 nM, displaced3H‐1α25‐dihydrxyvitamin D3from the membranes with 725 nM of the hormone displacing 40–49% of the radioactivity. Similarly, 1β,25‐dihydroxyvitamin D3, 7.25 nM and 72.5 nM, displaced 1α25‐dihydroxyvitamin D3binding while 25‐hydroxyvitamin D3, 7.25 nM, did not. The apparent dissociation constant (KD) for 1α25‐dihydroxyvitamin D3was detrermined from displacement of3H‐1α25‐dihydroxyvitamin D3yielding a value of 8.1 × 10−7M by Scatchard analysis. The KDfor the 1β epimer determine from displacement of3H‐1α25‐dihydroxyvitamin D3was 4.8 × 10−7M. The data suggest the presence of a receptor on the membrane of ROS 24/1 cells that reconize 1α25‐dihydroxyvitamin D3and its 1β epimer, but not 25‐dihydroxyvitamin D3. Its ability to reconize the 1β epimer which appears to be a specific anagonist of the rapid effect of the hormone suggests that these studies may be the initial steps in the isolation and characterization o

ISSN:0730-2312    

DOI:10.1002/jcb.240560411

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY