Parathyroid-hormone-related protein as a regulator of pRb and the cell cycle in arterial smooth muscle.
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.


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.
Fiaschi-Taesch
Nathalie
N
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
Takane
Karen K
KK
Masters
Sophia
S
Lopez-Talavera
Juan Carlos
JC
Stewart
Andrew F
AF
D000256:Adenoviridae / Q000235:genetics; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001013:Aorta, Thoracic; D020212:Carotid Artery Injuries / Q000628:therapy; D017536:Carotid Artery, Common; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division; D002460:Cell Line / Q000166:cytology / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D044162:Parathyroid Hormone-Related Protein / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D010769:Phosphothreonine / Q000032:analysis; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000502:physiology*; D014162:Transfection
D018076:DNA, Complementary; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D016160:Retinoblastoma Protein; D010769:Phosphothreonine; D010768:Phosphoserine