p21CIP1-mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene.
gax, a diverged homeobox gene expressed in vascular smooth muscle cells (VSMCs), is down-regulated in vitro by mitogen stimulation and in vivo in response to vascular injury that leads to cellular proliferation. Recombinant Gax protein microinjected into VSMCs and fibroblasts inhibited the mitogen-induced entry into S-phase when introduced either during quiescence or early stages of G1. Overexpression of gax with a replication-defective adenovirus vector resulted in G0/G1 cell cycle arrest of VSMCs and fibroblasts. The gax-induced growth inhibition correlated with a p53-independent up-regulation of the cyclin-dependent kinase inhibitor p21. Gax overexpression also led to an association of p21 with cdk2 complexes and a decrease in cdk2 activity. Fibroblasts deficient in p21 were not susceptible to a reduction in cdk2 activity or growth inhibition by gax overexpression. Localized delivery of the virus to denuded rat carotid arteries significantly reduced neointima formation and luminal narrowing. These data indicate that gax overexpression can inhibit cell proliferation in a p21-dependent manner and can modulate injury-induced changes in vessel wall morphology that result from excessive cellular proliferation.
Smith
R C
RC
Division of Cardiovascular Research, St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Branellec
D
D
Gorski
D H
DH
Guo
K
K
Perlman
H
H
Dedieu
J F
JF
Pastore
C
C
Mahfoudi
A
A
Denèfle
P
P
Isner
J M
JM
Walsh
K
K
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D042846:CDC2-CDC28 Kinases; D020212:Carotid Artery Injuries; D002455:Cell Division; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D016213:Cyclins / Q000502:physiology*; D003673:Defective Viruses / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018398:Homeodomain Proteins; C081336:Meox2 protein, rat; D009124:Muscle Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases