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Trendsetters

Novel Control of Urokinase Receptor Expression

Steven Idell

Department of Medical Specialities University of Texas Health Science Center at Tyler PO Box 2003 Tyler, TX 75710
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.

Heinz Valtin

Editor, TRENDSETTERS

The best-known function of urokinase is fibrinolysis. Urokinase is an enzyme that cleaves plasminogen to generate plasmin, which, in turn, degrades fibrin. Through its location at the cell surface, the urokinase receptor targets fibrinolytic activity. This receptor, however—either independently or via interaction with urokinase or other agonists—influences a number of other critical functions, such as cellular proliferation and differentiation, intracellular signaling, and cellular adhesion and motility. For example, Wei and associates (3) have reported that the urokinase receptor can form stable complexes with integrins and thereby modify cellular adhesion. The present précis deals with regulation of the urokinase receptor at the posttranscriptional level and how such regulation might influence remodeling of tissues and growth of tumors.

Regulation of a protein can occur either at the level of transcription of the gene in the nucleus or after the messenger RNA (mRNA) appears in the cytoplasm. Until recently, the posttranscriptional mechanism(s) by which expression of the urokinase receptor is controlled remained unclear. One possible such mechanism is an interaction between certain binding proteins and a specific region in the mRNA that codes for the urokinase receptor. This interaction would either stabilize or destabilize the message for the receptor and thereby influence its expression.

Shetty and colleagues have reported that mediators occurring in either the inflammatory microenvironment or in neoplastic stroma stabilized expression of the mRNA for the urokinase receptor. Inasmuch as the stabilization was observed even under experimental conditions when protein synthesis was blocked, the effect must have occurred at the posttranscriptional level and presumably involved a protein (1). Indeed, by conventional electrophoretic techniques, Shetty et al. (1) found that at least one of the mediators was a newly described protein that binds specifically to the mRNA that codes for the urokinase receptor (1).

The same group (1) then used a molecular approach to demonstrate that the binding protein acted by regulating the expression of the urokinase receptor mRNA. The rationale of their experiments was to create chimeric alterations of a ß-globin gene, which incorporated regions of the mRNA that bound the putative regulatory binding protein or control regions that did not bind this protein. Through such alterations in the stable ß-globin gene, they were able to show that attachment of the newly described protein to the binding site destabilized the mRNA for the urokinase receptor (1).

By means of a different molecular approach, these investigators showed that this posttranscriptional regulation could affect the number and function of the urokinase receptor at the cell surface (2). They showed that cells genetically engineered to overexpress the binding region on the receptor mRNA competed for the binding protein against unaltered binding sequences, thereby stabilizing the mRNA for the receptor (2). They found, furthermore, that increased expression of the urokinase receptor at the cell surface was associated with increased cellular proliferation and invasiveness.

The work reported by Shetty et al. (1, 2) extends our understanding of how the urokinase receptor is regulated at the posttranscriptional level. The work has demonstrated one mechanism by which the attachment of the newly described binding protein to the mRNA for the receptor might influence the growth of tumors. The results also raise the intriguing possibility that other components of the fibrinolytic system may be regulated in a similar manner.

References

1. Shetty, S., A. Kumar, and S. Idell. Posttranscriptional regulation of urokinase receptor mRNA: identification of a novel urokinase receptor mRNA binding protein in human mesothelioma cells. Mol. Cell. Biol. 17: 1075–1083, 1997.[Abstract]
2. Shetty, S. and S. Idell. A urokinase receptor mRNA binding protein-mRNA interaction regulates receptor expression and function in human pleural mesothelioma cells. Arch. Biochem. Biophys. 356: 265–279, 1998.[Medline]
3. Wei, Y., M. Lukashev, D. J. Simon, S. C. Bodary, S. Rosenberg, M. V. Doyle, and H. A. Chapman. Regulation of integrin function by the urokinase receptor. Science 273: 1551–1554, 1996.[Abstract]

Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only.

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