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Molecular and Cellular Biology, June 2000, p. 4309-4319, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The c-Myc Transactivation Domain Is a Direct Modulator of Apoptotic versus Proliferative Signals

David W. Chang,1 Gisela F. Claassen,2 Stephen R. Hann,2 and Michael D. Cole1,*

Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544,1 and Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 372322

Received 22 October 1999/Returned for modification 1 December 1999/Accepted 17 March 2000

We have assayed the oncogenic, proliferative, and apoptotic activities of the frequent mutations that occur in the c-myc gene in Burkitt's lymphomas. Some alleles have a modest (50 to 60%) increase in transforming activity; however, the most frequent Burkitt's lymphoma allele (T58I) had an unexpected substantial decrease in transforming activity (85%). All alleles restored the proliferation function of c-Myc in cells that grow slowly due to a c-myc knockout. There was discordance for some alleles between apoptotic and oncogenic activities, but only the T58A allele had elevated transforming activity with a concomitant reduced apoptotic potential. We discovered a novel missense mutation, MycS71F, that had a very low apoptotic activity compared to wild-type Myc, yet this mutation has never been found in lymphomas, suggesting that there is no strong selection for antiapoptotic c-Myc alleles. MycS71F also induced very low levels of cytochrome c release from mitochondria, suggesting a mechanism of action for this mutation. Phosphopeptide mapping provided a biochemical basis for the dramatically different biological activities of the transformation-defective T58I and transformation-enhanced T58A c-Myc alleles. Furthermore, the antiapoptotic survival factor insulin-like growth factor 1 was found to suppress phosphorylation of T58, suggesting that the c-Myc transactivation domain is a direct target of survival signals.

* Corresponding author. Mailing address: Department of Molecular Biology, Princeton University, Princeton, NJ 08544. Phone: (609) 258-5936. Fax: 609-258-2759. E-mail: mcole{at}molbio.princeton.edu.

Molecular and Cellular Biology, June 2000, p. 4309-4319, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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