Elfman F, Bok R, Conn M, Shuman M, Cunha G
Department of Anatomy, University of California, San Francisco 94143, USA.
Differentiation. 2001 Dec;69(2-3):108-20. doi: 10.1046/j.1432-0436.2001.690205.x.
The plasma membrane urokinase plasminogen activator receptor (uPAR) localizes and enhances activation of pro-uPA. Active uPA, in turn, promotes increased degradation of the extracellular matrix (ECM) by activation of plasminogen. uPAR binds to ECM molecules and integrins, which can affect cellular adhesion, signal transduction, and gene regulation. The current study examines the expression and function of uPAR in developing rat ventral prostates (VPs). We report that newborn VPs express uPAR mRNA and protein. In addition, the function of uPAR-bound uPA during in vitro prostatic development was studied by adding recombinant peptide competitive inhibitors of uPA-uPAR binding. Newborn VP explants were cultured in serum-free media for one week with 10(-8) M testosterone plus chimeric peptides containing a human immunoglobulin G Fc domain and either human uPA amino acids 1-138 (hu-uPA 1-138) as a control or mouse uPA amino acids 1-138 (mo-uPA 1-138) or 1-48 (mo-uPA 1-48). Hu-uPA 1-138-treated VPs underwent normal ductal branching morphogenesis and tissue differentiation. In contrast, VPs treated with mo-uPA 1-138 or mo-uPA 1-48 displayed a dose-dependent perturbation of ductal branching. Differentiation of both epithelial and mesenchymal tissues was also impaired. Mo-uPA 1-48-treated VPs contained significantly more apoptotic cells. These observations suggest that disruption of uPA binding to uPAR results in a retardation of the development of newborn VPs.
质膜尿激酶型纤溶酶原激活物受体（uPAR）可使尿激酶原（pro - uPA）定位并增强其激活作用。反过来，活性尿激酶型纤溶酶原激活物（uPA）通过激活纤溶酶原促进细胞外基质（ECM）降解增加。uPAR与ECM分子及整合素结合，这会影响细胞黏附、信号转导和基因调控。本研究检测了uPAR在发育中的大鼠腹侧前列腺（VP）中的表达及功能。我们发现新生VP表达uPAR mRNA和蛋白。此外，通过添加uPA - uPAR结合的重组肽竞争性抑制剂，研究了uPAR结合的uPA在体外前列腺发育过程中的功能。将新生VP外植体在无血清培养基中培养一周，培养基中含有10⁻⁸ M睾酮以及嵌合肽，该嵌合肽含有人类免疫球蛋白G Fc结构域以及作为对照的人uPA氨基酸1 - 138（hu - uPA 1 - 138）或小鼠uPA氨基酸1 - 138（mo - uPA 1 - 138）或1 - 48（mo - uPA 1 - 48）。经hu - uPA 1 - 138处理的VP经历了正常的导管分支形态发生和组织分化。相反，经mo - uPA 1 - 138或mo - uPA 1 - 48处理的VP表现出导管分支的剂量依赖性扰动。上皮和间充质组织的分化也受到损害。经mo - uPA 1 - 48处理的VP含有明显更多的凋亡细胞。这些观察结果表明，uPA与uPAR结合的破坏导致新生VP发育迟缓。
