Id2 mediates tumor initiation, proliferation, and angiogenesis in Rb mutant mice.
The inhibitor of differentiation Id2 is a target of the retinoblastoma (Rb) protein during mouse embryogenesis. In Rb(+/-) mice, LOH at the wild-type Rb allele initiates pituitary adenocarcinoma, a tumor derived from embryonic melanotropes. Here we identify a critical role for Id2 in initiation, growth, and angiogenesis of pituitary tumors from Rb(+/-) mice. We show that proliferation and differentiation are intimately coupled in Rb(+/-) pituitary cells before tumor initiation. In Id2-null pituitaries, premature activation of basic helix-loop-helix-mediated transcription and expression of the cdk inhibitor p27(Kip1) impairs the proliferation of melanotropes and tumor initiation. Without Id2, Rb(+/-) mice have fewer early tumor lesions and a markedly decreased proliferation rate of the tumor foci. Expression of Id2 by pituitary tumor cells promotes growth and angiogenesis by functioning as a master regulator of vascular endothelial growth factor (VEGF). In human neuroblastoma, the N-Myc-driven expression of Id2 is sufficient and necessary for expression of VEGF. These results establish that aberrant Id2 activity directs initiation and progression of embryonal cancer.
Lasorella
Anna
A
Institute for Cancer Genetics, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
Rothschild
Gerson
G
Yokota
Yoshifumi
Y
Russell
Robert G
RG
Iavarone
Antonio
A
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056746:Cyclin G; D056766:Cyclin G1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051797:Inhibitor of Differentiation Protein 2; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D010902:Pituitary Gland / Q000473:pathology; D010911:Pituitary Neoplasms / Q000098:blood supply / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004268:DNA-Binding Proteins; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D050760:Cyclin-Dependent Kinase Inhibitor p27