Urokinase receptor in intracellular proteolysis: role for the DNA damage in cancer and vascular aging

• Applicant: Dr. Yulia Kiyan
• Subject Area: Nephrology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 160650722

Epidemiological studies have shown that age is the chief risk factor for occlusive cardiovascular diseases, but the molecular mechanisms that underlie the increase in risk conferred by aging remain unclear. Evidence suggests that ageassociated cardiovascular dysfunction is associated with alteration of vascular smooth muscle cell (VSMC) physiology. Urokinase-type plasminogen activator (uPA) and its specific receptor (uPAR) have been implicated in a broad spectrum of pathophysiological processes involved in cardiovascular diseases and vascular remodeling. Yet, a role of the uPA/uPAR system in vascular aging has not been investigated. Based on our recent research, we hypothesize that aging up-regulates expression of uPAR in VSMC that modifies cell fate decreasing cell proliferation, ability for re-differentiation, initiating apoptosis and leading finally to VSMC premature senescence. We further hypothesize that these effects involve at the cellular level selective uPAR-directed activation of regulatory mechanisms, in particular, phosphorylation of retinoblastoma protein (pRb1), SUMOylation of promyelocytic leukemia nuclear body (PLM) proteins, the tumor suppressor p53, and/or telomerase activity. Our findings point to a key role of the protein tyrosine kinase SHP-2 in these processes. Targeting of these components is potentially an attractive strategy for the treatment of aging-associated vascular diseases in an aging population.

• DFG Programme: Research Grants