You are not currently logged in.
Access your personal account or get JSTOR access through your library or other institution:
If You Use a Screen ReaderThis content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Egr1 mediates p53-independent c-Myc—induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism
David N. Boone, Ying Qi, Zhaoliang Li, Stephen R. Hann and Klaus Bister
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 2 (January 11, 2011), pp. 632-637
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25770833
Page Count: 6
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Preview not available
c-Myc is frequently deregulated in human cancers. Although deregulated c-Myc leads to tumor growth, it also triggers apoptosis in partnership with tumor suppressors such as ARF and p53. Apoptosis induced by c-Myc is a critical fail-safe mechanism for the cell to protect against unrestrained proliferation. Despite the plethora of information on c-Myc, the molecular mechanism of how c-Myc induces both transformation and apoptosis is unclear. Oncogenic c-Myc can indirectly induce the expression of the tumor suppressor ARF, which leads to apoptosis through the stabilization of p53, but both c-Myc and ARF have apoptotic activities that are independent of p53. In cells without p53, ARF directly binds to c-Myc protein and inhibits c-Myc—induced hyperproliferation and transformation with a concomitant inhibition of canonical c-Myc target gene induction. However, ARF is an essential cofactor for p53-independent c-Myc—induced apoptosis. Here we show that ARF is necessary for c-Myc to drive transcription of a unique noncanonical target gene, Egr1. In contrast, c-Myc induces another family member, Egr2, through a canonical mechanism that is inhibited by ARF. We further demonstrate that Egr1 is essential for p53-independent c-Myc—induced apoptosis, but not ARF-independent c-Myc—induced apoptosis. Therefore, ARF binding switches the inherent activity of c-Myc from a proliferative to apoptotic protein without p53 through a unique noncanonical transcriptional mechanism. These findings also provide evidence that cofactors can differentially regulate specific transcriptional programs of c-Myc leading to different biological outcomes.
Proceedings of the National Academy of Sciences of the United States of America © 2011 National Academy of Sciences