The regulation of plasminogen activation involves genes for two plasminogen activators (tissue type and urokinase type), two specific inhibitors (type 1 and type 2), and a membrane-anchored urokinase-type plasminogen-activator-specific receptor. This system plays an important role in various biological processes involving extracellular proteolysis. Recent studies have revealed that the system, through interplay with integrins and the extracellular matrix protein vitronectin, is also involved in the regulation of cell migration and proliferation in a manner independent of proteolytic activity. The genes are expressed in many different cell types and their expression is under the control of diverse extracellular signals. Gene expression reflects the levels of the corresponding mRNA, which should be the net result of synthesis and degradation. Thus, modulation of mRNA stability is an important factor in overall regulation. This review summarizes current understanding of the biology and regulation of genes involved in plasminogen activation at different levels.
The human c-myc proto-oncogene, implicated in the control of many cellular processes including cell growth and apoptosis, encodes three isoforms which differ in their N-terminal region. The functions of these isoforms have never been addressed in vivo. Here, we used Drosophila melanogaster to examine their functions in a fully integrated system. First, we established that the human c-Myc protein can rescue lethal mutations of the Drosophila myc ortholog, dmyc, demonstrating the biological relevance of this model. Then, we characterized a new lethal dmyc insertion allele, which permits expression of human c-Myc in place of dMyc and used it to compare physiological activities of these isoforms in whole-organism rescue, transcription, cell growth, and apoptosis. These isoforms differ both quantitatively and qualitatively. Most remarkably, while the small c-MycS form truncated for much of its N-terminal trans-activation domain efficiently rescued viability and cell growth, it did not induce detectable programmed cell death. Our data indicate that the main functional difference between c-Myc isoforms resides in their apoptotic properties and that the N-terminal region, containing the conserved MbI motif, is decisive in governing the choice between growth and death.
Myc proteins are essential regulators of cellular growth and proliferation during normal development. Activating mutations in myc genes result in excessive growth and are frequently associated with human cancers. At the same time, forced expression of Myc sensitizes vertebrate cells towards different pro-apoptotic stimuli. Recently, the ability of overexpressed Myc to induce cell-autonomous apoptosis has been shown to be evolutionarily conserved in Drosophila Myc (dMyc). Here, we show that dMyc induced apoptosis is accompanied by the induction of Drosophila p53 mRNA, but that dp53 activity is not essential for dMyc's ability to induce apoptosis. Conversely, larvae carrying a hypomorphic dmyc mutation are more resistant to the apoptosis-promoting effects of X-irradiation. These data suggest that the control of apoptosis is a physiological function of Myc and that dMyc might play a role in the response to DNA damage.
In LLC-PK, cells, urokinase-type plasminogen activator (uPA) mRNA has a short half-life of 70 min. We have previously demonstrated that most of the regulatory regions responsible for the rapid turnover of uPA mRNA in LLC-PK, cells reside in its 3' untranslated region (3' UTR), where there are at least three regulatory sites, one of which is A+U-rich. This A+U-rich sequence mediates uPA mRNA stabilization induced by protein kinase C (PKC) down-regulation. In this work, we found that uPA mRNA is rather stable in MDA-MB-231 cells with a half-life of 17 h. We compared the stability of hybrid globin mRNA containing different parts of uPA mRNA in its 3' UTR and found that the A+U-rich sequence of uPA mRNA renders otherwise stable globin mRNA unstable in LLC-PK, cells but not in MDA-MB-231 cells. We identified a cytoplasmic protein of 40 kDa (p40) which specifically interacts with the A+U-rich sequence. Levels of p40 activity as detected by ultraviolet cross-linking were higher in MDA-MB-231 and PKC-down-regulated LLC-PK, cells than in untreated LLC-PK, cells. Prior treatment of the cytoplasm with a specific antibody against heterogeneous nuclear ribonucleoprotein C (hnRNP C) significantly reduced p40 activity. These results suggest a correlation between the A+U-rich sequence-dependent uPA mRNA stabilization in vivo and the binding of hnRNP C to the A+U-rich sequence in vitro.
GTP stimulation of adenylyl cyclase from the dimorphi¢ pathogenic fungus Candida afbicans is greatly enhanced by preincubation of membrane proteins with cholera toxin, NAD and ATP. In the presence of [s"P]NAD the toxin catalyzes the covalent incorporation of radioactivity into a membrane protein of 40 kDa. Pertussis toxin catalyzes the transference of the radioactivity from [s-'P]NAD to a 32 kDa protein. Two major proteins of 40--42 and 30-32 kDa ,:an also be recognized in Western blots by an anti G~-common antibody. The results support .'he idea that G proteins are part of the bormonesensory transduction chain of Candida [(1990) Bioehem. Biophys. Res.
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