The epithelial-to-mesenchymal transition (EMT) is a crucial process, occurring both during development and tumor progression, by which an epithelial cell undergoes a conversion to a mesenchymal phenotype, dissociates from initial contacts and migrates to secondary sites. We recently reported that in hepatocytes the multifunctional cytokine TGFbeta induces a full EMT characterized by (i) Snail induction, (ii) E-cadherin delocalization and down-regulation, (iii) down-regulation of the hepatocyte transcriptional factor HNF4alpha and (iv) up-regulation of mesenchymal and invasiveness markers. In particular, we showed that Snail directly causes the transcriptional down-regulation of E-cadherin and HNF4, while it is not sufficient for the up-regulation of mesenchymal and invasiveness EMT markers. In this paper, we show that in hepatocytes TGFbeta induces a Src-dependent activation of the focal adhesion protein FAK. More relevantly, we gathered results indicating that FAK signaling is required for (i) transcriptional up-regulation of mesenchymal and invasiveness markers and (ii) delocalization of membrane-bound E-cadherin. Our results provide the first evidence of FAK functional role in TGFbeta-mediated EMT in hepatocytes.
By virtue of its greater safety and less trauma to tissues than percutaneous techniques, TLT can also be carried out in infants and children (an important benchmark for any tracheostomy technique) and in very difficult patients from whom other techniques have serious drawbacks.
The binding site of human factor XI1 (FXII) for negatively charged surfaces has been proposed to be localized in the N-terminal region of factor XII. We have generated two recombinant factor XI1 proteins that lack this region : one protein consisting of the second growth-factor-like domain, the kringle domain, the proline-rich region and the catalytic domain of FXII (rFXII-U-like), and another consisting of only 16 amino acids of the proline-rich region of the heavy-chain region and the catalytic domain (rFXII-lpc). Each recombinant truncated protein, as well as recombinant full-length FXII (rFXII), were produced in HepG2 cells and purified by immunoaffinity chromatography. The capability of these recombinant proteins to bind to negatively charged surfaces and to initiate contact activation was studied. Radiolabeled rFXII-U-like and, to a lesser extent, rFXTT-lpc bound to glass in a concentration-dependent manner, yet with lower efficiency than rFXII. The binding of the recombinant proteins was inhibited by a 100-fold molar excess of non-labeled native factor XII. On native polyacrylamide gel electrophoresis, both truncated proteins appeared to bind also to dextran sulfate, a soluble negatively charged compound. Glassbound rFXII-U-like was able to activate prekallikrein in FXII-deficient plasma (assessed by measuring the generation of kallikrein-C1-inhibitor complexes), but less efficiently than rFXII. rFXIT-U-like and rFXII-lpc exhibited coagulant activity, but this activity was significantly lower than that of rFXII. These data confirm that the N-terminal part of the heavy-chain region of factor XI1 contains a binding site for negatively charged activating surfaces, and indicate that other sequences, possibly located on the second epidermal-growth-factor-like domain and/or the kringle domain, contribute to the binding of factor XI1 to these surfaces.
Fetal mouse erythropoiesis proceeds initially in yolk-sac blood islands (8 to 12 days) and, subsequently, in liver (12 to at least 16 days). Yolksac cells synthesize three hemoglobins, Hb E(I), Hb E(II) and Hb E(III). Hb E(I) has x- and y-globin chains; Hb E(II) has alpha and y; HB E(III), alpha and z. No detectable beta-globin is formed in these cells. Liver erythroid cells form only adult hemoglobin, composed of alpha- and beta-chains.
Transcription of U2 small nuclear RNA (snRNA) genes in eukaryotes is executed by RNA polymerase II and is dependent on extragenic cis-acting regulatory sequences which are not found in other genes. Here we have mapped promoter elements of the Trypanosoma brucei U2 snRNA gene by transient DNA expression of mutant constructs in insect form trypanosomes. Unlike other eukaryotic U2 snRNA genes, the T. brucei homolog is transcribed by an RNA polymerase III-like enzyme on the basis of its sensitivity to the inhibitors ot-amanitin and tagetitoxin. Thus, the trypanosome U2 snRNA provides a unique example of an RNA polymerase III transcript carrying a trimethylated cap structure. The promoter of this gene consists of three distinct elements: an intragenic sequence close to the 5' end of the coding region, which is probably required to position the polymerase at the correct transcription start site; and two extragenic elements, located 110 and 160 nucleotides upstream, which are essential for U2 snRNA gene expression. These two elements closely resemble both in sequence and in distance from each other the A and B box consensus sequences of the internal control regions of tRNA genes. (203) 785-3864. t Permanent address: Department of Human Biopathology, University of Rome, La Sapienza, 00100 Rome, Italy.into the 5'-flanking region of the U2 snRNA gene, the specificity of the U2 promoter switches from RNA polymerase II to RNA polymerase III.Promoter elements of invertebrate U-snRNA genes have not yet been analyzed in such detail. Expression of the sea urchin U1 snRNA gene requires a DSE located between -318 and -300 and a PSE centered at -55 (41). On the other hand, the sea urchin U2 snRNA gene contains four cis-acting elements, including a TATA box at -25 and a PSE at -55 (30). Since there is no similarity between the regulatory elements required for expression of the sea urchin Ul and U2 snRNA genes, it appears that each sea urchin U-snRNA gene utilizes distinct promoter elements.In contrast, in higher plants the promoter elements for the RNA polymerase II-and RNA polymerase III-transcribed U-snRNA genes are identical (38,40 (27,42). Immunoprecipitations with antibodies against the trimethylated cap structure of U-snRNAs have identified a number of possible candidates for U-snRNAs in trypanosomes (25,33). Of these, four have been characterized in more detail, and on the basis of structural homology with other eukaryotic U-snRNAs, three have been identified as U2, U4, and U6 snRNAs (25,32,33
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