RB2/p130 gene-enhanced expression down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in vivo.
Angiogenesis is an essential step in the progression of tumor formation and development. The switch to an angiogenetic phenotype can occur as a distinct step before progression to a neoplastic phenotype and is linked to genetic changes such as mutations in key cell cycle regulatory genes. The pathogenesis of the angiogenetic phenotype may involve the inactivation of tumor suppressor genes such as the "guardian of the genome," p53, and the cyclin-dependent kinase inhibitor p16. Retinoblastoma family member RB2/p130 encodes a cell cycle regulatory protein and has been found mutated in different tumor types. Overexpression of RB2/p130 not only suppresses tumor formation in nude mice but also causes regression of established tumor grafts, suggesting that RB2/p130 may modulate the angiogenetic balance. We found that induction of RB2/p130 expression using a tetracycline-regulated gene expression system as well as retroviral and adenoviral-mediated gene delivery inhibited angiogenesis in vivo. This correlated with pRb2/p130-mediated down-regulation of vascular endothelial growth factor protein expression both in vitro and in vivo.
Claudio
P P
PP
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Stiegler
P
P
Howard
C M
CM
Bellan
C
C
Minimo
C
C
Tosi
G M
GM
Rak
J
J
Kovatich
A
A
De Fazio
P
P
Micheli
P
P
Caputi
M
M
Leoncini
L
L
Kerbel
R
R
Giordano
G G
GG
Giordano
A
A
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D007120:Immunochemistry; D008222:Lymphokines / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011506:Proteins; D012313:RNA / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010750:Phosphoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011506:Proteins; C493837:RBL2 protein, human; C493838:Rbl2 protein, mouse; D050717:Retinoblastoma-Like Protein p130; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012313:RNA