OPPOSING MITOGENIC AND ANTI-MITOGENIC ACTIONS OF PARATHYROID HORMONE-RELATED PROTEIN IS VASCULAR SMOOTH-MUSCLE CELLS - A CRITICAL ROLE FOR NUCLEAR TARGETING

Parathyroid hormone-related protein (PTHrP) is a prohormone that is po sttranslationally-processed to a family of mature secretory forms, eac h of which has its own cognate receptor(s) on the cell surface that me diate the actions of PTHrP. In addition to being secreted via the clas sical secretory pathway and interacting with cell surface receptors in a paracrine/autocrine fashion, PTHrP appears to be able to enter the nucleus directly following translation and influence cellular events i n an ''intracrine'' fashion, In this report, wt demonstrate that PTHrP can be targeted to the nucleus In vascular smooth muscle cells, that this nuclear targeting is associated with a striking increase In mirog enesis, that this nuclear effect on proliferation is the diametric opp osite of the effects of PTHrP resulting front interaction with cell su rface receptors on vascular smooth muscle cells, and that the regions of the PTHrP sequence responsible for this nuclear targeting represent a classical bipartite nuclear localization signal. This report descri bes the activation of the cell cycle in association with nuclear local ization of PTHrP in any cell type, These findings have important impli cations for the normal physiology of PTHrP in the many tissues which p roduce it, and suggest that gene delivery of PTHrP or modified variant s may be useful in the management of atherosclerotic vascular disease.