The Regulation of UPA and UPAR in Human Carcinoma Cells

描述（由申请人提供）：在各种恶性肿瘤中检测到尿激酶纤溶酶原激活物（uPA）及其受体（uPAR）的过表达。体内外研究表明uPA/uPAR在肿瘤的发生、发展和转移中起重要作用。然而，uPA/uPAR在侵袭性癌细胞中过度表达的机制仍不清楚。在我们早期的研究中，我们发现1）组成型p38 MAPK活性是uPA/uPAR mRNA稳定所必需的; 2）α v整合素表达是p38活性和uPA表达升高所必需的; 3）α v整合素连接激活p38并上调侵袭性癌细胞中uPA的表达。我们的初步研究进一步证实了Rac 1/Cdc 42-PAK 1-MKK 3信号通路在α v整合素介导的p38激活中起重要作用，MAPKAPK 2是p38下游调控uPA mRNA稳定性的主要效应子，uPA 3 '-UTR中富含AU的元件（ARE）是p38调控uPA mRNA稳定性所必需的; 4）TTP，ARE结合蛋白，使uPA mRNA稳定性不稳定，并且是p38和MAPKAPK 2的直接底物。该建议旨在进一步表征uPA/uPAR的过表达在侵袭性癌细胞中维持的机制。建议的研究由四个具体目标组成：1。α v整联蛋白亚基胞质尾区在α v整联蛋白介导的p38激活和uPAIuPAR上调中的作用2. Rho GTP酶和PAK 1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p38 α、uPA和uPAR特异性核酶抑制癌细胞转移的功效这些研究将增加我们对alphav整合素介导的信号传导、p38介导的mRNA稳定性以及uPA/uPAR在侵袭性癌细胞中高表达机制的理解。明确uPA/uPAR表达的机制有助于设计更好的治疗方法来抑制肿瘤细胞的侵袭和转移。

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.