Abstract
To explore the role of c-Myc in carcinogenesis, we have developed a reversible transgenic model of pancreatic beta cell oncogenesis using a switchable form of the c-Myc protein. Activation of c-Myc in adult, mature beta cells induces uniform beta cell proliferation but is accompanied by overwhelming apoptosis that rapidly erodes beta cell mass. Thus, the oncogenic potential of c-Myc in beta cells is masked by apoptosis. Upon suppression of c-Myc-induced beta cell apoptosis by coexpression of Bcl-x(L), c-Myc triggers rapid and uniform progression into angiogenic, invasive tumors. Subsequent c-Myc deactivation induces rapid regression associated with vascular degeneration and beta cell apoptosis. Our data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.
MeSH terms
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3T3 Cells
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Animals
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Apoptosis / genetics
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Apoptosis / physiology*
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Cadherins / genetics
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Cadherins / metabolism
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Cell Division
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Cell Line
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Cell Nucleus / metabolism
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Estrogen Antagonists / pharmacology
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Genes, myc / genetics
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Genes, myc / physiology
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Humans
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Insulinoma / genetics
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Insulinoma / pathology
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Islets of Langerhans / metabolism
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Islets of Langerhans / pathology
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Mutation
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Pancreatic Neoplasms / genetics*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / physiology*
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Receptors, Estrogen / metabolism
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Tamoxifen / analogs & derivatives*
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Tamoxifen / pharmacology
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bcl-X Protein
Substances
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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Cadherins
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Estrogen Antagonists
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Receptors, Estrogen
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bcl-X Protein
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Tamoxifen
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afimoxifene