The Regulation of UPA and UPAR in Human Carcinoma Cells

描述（由申请人提供）：尿激酶纤溶酶原激活剂（uPA）及其受体（uPAR）的过表达在多种恶性肿瘤中被检测到。体外和体内研究均表明，uPA/uPAR在肿瘤进展和转移中发挥重要作用。然而，侵袭性癌细胞中uPA/uPAR过表达的机制尚不清楚。在我们的早期研究中，我们发现1)组成性p38 MAPK活性是稳定uPA/uPAR mRNA所必需的；2) av整合素的表达对p38活性和uPA表达的升高至关重要；3)在侵袭性癌细胞中，av整合连接激活p38并上调uPA的表达。在我们的初步研究中，我们进一步证明了1)涉及Rac1/Cdc42-PAK1-MKK3的信号通路对av整合素介导的p38激活很重要；2) MAPKAPK2是p38下游调控uPA mRNA稳定性的主要效应子；3) upa3 '-UTR中的富au元素（ARE）对p38调控的uPA mRNA稳定性至关重要；4) TTP，一种ARE结合蛋白，破坏了uPA mRNA的稳定性和p38和MAPKAPK2的直接底物。本研究旨在进一步表征uPA/uPAR在侵袭性癌细胞中维持过表达的机制。拟议的研究包括四个具体目标：1。整合素亚基细胞质尾部在整合素介导的p38激活和uPAIuPAR上调中的作用。2. Rho GTPases和PAK1在av介导的p38激活和uPA/uPAR上调中的作用。3. p38调控uPA/uPAR mRNA稳定性的机制。4. 腺病毒递送的p38α、uPA和upar特异性核酶抑制癌细胞转移的效果。这些研究将增加我们对侵袭性癌细胞中α - v整合素介导的信号传导、p38介导的mRNA稳定以及uPA/uPAR高表达机制的理解。更好地确定uPA/uPAR表达的机制可能有助于设计更好的治疗方法来抑制癌细胞的侵袭和转移。

DESCRIPTION (provided by applicant): The overexpression of urokinase plasminogen activator (uPA) and its receptor (uPAR) is detected in various malignancies. Both in vitro and in vivo studies demonstrate that uPA/uPAR play important role in tumor progression and metastasis. However, the mechanisms responsible for uPA/uPAR overexpression in invasive cancer cells remain unclear. In our early studies, we found that 1) the constitutive p38 MAPK activity is required for the stabilization of uPA/uPAR mRNA; 2) av integrin expression is essential for elevated p38 activity and uPA expression; 3) av integnn ligation activates p38 and upregulates uPA expression in invasive cancer cells. In our preliminary studies, we further demonstrated that 1) a signaling pathway involving Rac1/Cdc42-PAK1-MKK3 is important for av integrin-mediatedp38 activation; 2) MAPKAPK2 is a main p38 downstream effector for regulating uPA mRNA stability; 3) The AU-rich element (ARE) in uPA 3'-UTR is essential for p38-regulated uPA mRNA stability; 4) TTP, an ARE binding protein, destabilizes uPA mRNA stability and a direct substrate of p38 and MAPKAPK2. This proposal seeks to further characterize the mechanisms by which the overexpression of uPA/uPAR is maintained in invasive cancer cells. The proposed studies are composed of four specific aims: 1. Role of the cytoplasmic tail of av integrin subunit in alphav integrin-mediated p38 activation and uPAIuPAR upregulation. 2. Role of Rho GTPases and PAK1 in av-mediated p38 activation and uPA/uPAR upregulation. 3. The mechanisms involved in p38-regulated uPA/uPAR mRNA stability. 4. Efficacy of adenovirus-delivered p38alpha, uPA and uPAR-specific ribozymes to suppress cancer cell metastasis. These studies will increase our understanding on alphav integrin-mediated signaling, p38-mediated mRNA stabilization and mechanisms involved in high uPA/uPAR expression in invasive cancer cells. Better defining the mechanism on uPA/uPAR expression may help design better therapeutic approaches to suppress cancer cell invasion and metastasis.