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Modulation of c-Myc Activity and Apoptosis in Vivo¹

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305

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.

¹ This work was supported by a Howard Hughes Young Investigator Award (to A. J. G.), a Lazard Faculty Scholarship (to S. J. K.), a Biomedical Research Support grant (to S. J. K.), NIH Grant CA64489-01 (to A. J. G.), and NIH Grant CA67166-01 (to A. J. G.). Thomas Graeber is a Fannie and John Hertz Predoctoral fellow, and Brent Rupnow is a Howard Hughes Medical Institute Predoctoral Fellow.

² To whom requests for reprints should be addressed.

Received 7/31/96. Accepted 8/16/96.

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