Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Cycle Proteins / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Cell Line, Tumor
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Cell Proliferation
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Cyclin G
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Cyclin G1
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Inhibitor of Differentiation Protein 2
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Mice
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Mice, Mutant Strains
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Mutation / genetics
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Neovascularization, Pathologic / genetics*
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Neuroblastoma / genetics*
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Pituitary Gland / pathology
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Pituitary Neoplasms / blood supply
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Pituitary Neoplasms / genetics*
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Retinoblastoma Protein / genetics*
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Retinoblastoma Protein / physiology
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tumor Suppressor Proteins / metabolism
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Vascular Endothelial Growth Factor A / metabolism*
Substances
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CCNG1 protein, human
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Ccng1 protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin G
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Cyclin G1
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Cyclins
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DNA-Binding Proteins
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Idb2 protein, mouse
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Inhibitor of Differentiation Protein 2
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Repressor Proteins
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Retinoblastoma Protein
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Transcription Factors
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A
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Cyclin-Dependent Kinase Inhibitor p27