The Regulation of UPA and UPAR in Human Carcinoma Cells

  • Huang, Shuang, (PI)

Project: Research project

Description

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.
StatusFinished
Effective start/end date12/1/015/31/12

Funding

  • National Institutes of Health: $232,488.00
  • National Institutes of Health: $232,554.00
  • National Institutes of Health: $307,895.00
  • National Institutes of Health: $307,895.00
  • National Institutes of Health: $307,895.00
  • National Institutes of Health: $232,554.00
  • National Institutes of Health: $302,878.00
  • National Institutes of Health: $232,554.00
  • National Institutes of Health: $307,895.00

Fingerprint

Plasminogen Activators
Urokinase-Type Plasminogen Activator
Carcinoma
RNA Stability
p38 Mitogen-Activated Protein Kinases
Neoplasms
Messenger RNA
AU Rich Elements
Neoplasm Metastasis
Integrin alphaV
Integrins
Urokinase Plasminogen Activator Receptors
Up-Regulation

Keywords

  • Medicine(all)