Document Detail


Parathyroid-hormone-related protein as a regulator of pRb and the cell cycle in arterial smooth muscle.
MedLine Citation:
PMID:  15210588     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Parathyroid hormone-related protein (PTHrP), a normal product of arterial vascular smooth muscle (VSM), contains a nuclear localization signal (NLS) and at least 2 translational initiation sites, one that generates a conventional signal peptide and one that disrupts the signal peptide. These unusual features allow PTHrP either to be secreted in a paracrine/autocrine fashion, and thereby to inhibit arterial smooth muscle proliferation, or to be retained within the cytosol and to translocate into the nucleus, thereby serving as an intracrine stimulator of smooth muscle proliferation. METHODS AND RESULTS: Here, we demonstrate 2 important findings. First, PTHrP dramatically increases the percentage of VSM cells in the S and in G2/M phases of the cell cycle. These effects require critical serine and threonine residues at positions Ser119, Ser130, Thr132, and Ser138 in the carboxy-terminus of PTHrP and are associated with the phosphorylation of the key cell cycle checkpoint regulator retinoblastoma protein, pRb. Second, because PTHrP devoid of the NLS serves as an inhibitor of VSM proliferation, we hypothesized that local delivery of NLS-deleted PTHrP to the arterial wall at the time of angioplasty might prevent neointimal hyperplasia. As hypothesized, using a rat carotid angioplasty model, adenoviral delivery of NLS-deleted PTHrP completely abolished the development of the neointima after angioplasty. CONCLUSIONS: PTHrP interacts with key cell cycle regulatory pathways within the arterial wall. Moreover, NLS-deleted PTHrP delivered to the arterial wall at the time of angioplasty seems to have promise as an agent that could reduce or eliminate the neointimal response to angioplasty.
Authors:
Nathalie Fiaschi-Taesch; Karen K Takane; Sophia Masters; Juan Carlos Lopez-Talavera; Andrew F Stewart
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-06-21
Journal Detail:
Title:  Circulation     Volume:  110     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-07-13     Completed Date:  2005-01-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  177-85     Citation Subset:  AIM; IM    
Affiliation:
Division of Endocrinology and Metabolism, BST E-1140, Endocrinology, University of Pittsburgh School of Medicine, 3550 Terrace St, Pittsburgh, PA 15213, USA. taeschn@msx.dept-med.pitt.edu
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Angioplasty, Balloon / adverse effects
Animals
Aorta, Thoracic
Carotid Artery Injuries / therapy
Carotid Artery, Common
Cell Cycle / drug effects,  physiology
Cell Division
Cell Line / cytology,  drug effects
DNA, Complementary / genetics
Gene Therapy
Genetic Vectors / administration & dosage,  therapeutic use
Male
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / cytology,  drug effects
Parathyroid Hormone-Related Protein / chemistry,  genetics,  physiology*
Peptide Fragments / physiology
Phosphorylation
Phosphoserine / analysis
Phosphothreonine / analysis
Protein Processing, Post-Translational
Protein Transport
Rats
Rats, Sprague-Dawley
Retinoblastoma Protein / physiology*
Transfection
Grant Support
ID/Acronym/Agency:
R-01-54308//PHS HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/Parathyroid Hormone-Related Protein; 0/Peptide Fragments; 0/Retinoblastoma Protein; 1114-81-4/Phosphothreonine; 17885-08-4/Phosphoserine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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