Suppression of Myc-induced Apoptosis in Beta Cells Exposes Multiple Oncogenic Properties of Myc and Triggers Carcinogenic Progression

Cell. 2002 May 3;109(3):321-34. doi: 10.1016/s0092-8674(02)00738-9.

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.

Publication types

  • Comparative Study

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Division
  • Cell Line
  • Cell Nucleus / metabolism
  • Estrogen Antagonists / pharmacology
  • Genes, myc / genetics
  • Genes, myc / physiology
  • Humans
  • Insulinoma / genetics
  • Insulinoma / pathology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Mutation
  • Pancreatic Neoplasms / genetics*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / physiology*
  • Receptors, Estrogen / metabolism
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / pharmacology
  • bcl-X Protein

Substances

  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Cadherins
  • Estrogen Antagonists
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Receptors, Estrogen
  • bcl-X Protein
  • Tamoxifen
  • afimoxifene