Modulation of c-Myc activity and apoptosis in vivo.
We have developed an animal tumor model system to study the effects of c-Myc activation on apoptosis induction in vivo. Tumors were generated in SCID mice from Rat-1 fibroblasts that constitutively express an inactive c-Myc-estrogen receptor fusion protein (T.D. Littlewood et al, Nucleic Acids Res., 23: 1686 -1690, 1995), which is activated in vivo by the administration of 4-hydroxytamoxifen in time release pellets. We demonstrate that activation of c-Myc results in a substantial increase in the number of apoptotic tumor cells and that this apoptosis is predominant in regions of tumor hypoxia. c-Myc-induced apoptosis of hypoxic cells is inhibited in tumors that overexpress the human Bcl-2 protein. Bcl-2, however, does not prevent p53 protein accumulation or the down-regulation of the cyclin-cdk inhibitor p27 protein following c-Myc activation by 4-hydroxytamoxifen. This result suggests that Bcl-2 does not affect c-Myc function directly but acts downstream of c-Myc to inhibit apoptosis. We propose that the ability of activated c-Myc to enhance cellular proliferation might contribute to the genesis of early neoplasms that are held in check by the alternate ability of c-Myc to induce apoptosis of cells that have outgrown their supply of oxygen or other factors associated with hypoxic regions of solid tumors. Secondary genetic lesions downstream of c-Myc that suppress the apoptotic potential of tumor cells, such as Bcl-2 overexpression, might play an important role in the malignant progression of these tumors because they would disrupt the balance between apoptosis and proliferation initiated by c-Myc deregulation.
Alarcon
R M
RM
Department of Radiation Oncology, Stanford University School of Medicine, California 94305, USA.
Rupnow
B A
BA
Graeber
T G
TG
Knox
S J
SJ
Giaccia
A J
AJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004965:Estrogen Antagonists / Q000494:pharmacology; D005347:Fibroblasts / Q000473:pathology / Q000637:transplantation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D004965:Estrogen Antagonists; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D050760:Cyclin-Dependent Kinase Inhibitor p27; C016601:afimoxifene