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Molecular and Cellular Biology, August 2000, p. 6008-6018, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Induction of Cell Cycle Progression and Acceleration of Apoptosis Are Two Separable Functions of c-Myc: Transrepression Correlates with Acceleration of Apoptosis

Suzanne D. Conzen,dagger Kathrin Gottlob, Eugene S. Kandel, Pratibha Khanduri, Andrew J. Wagner,Dagger Maura O'Leary, and Nissim Hay*

Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607

Received 25 February 2000/Returned for modification 10 April 2000/Accepted 17 May 2000

Analysis of amino-terminus mutants of c-Myc has allowed a systematic study of the interrelationship between Myc's ability to regulate transcription and its apoptotic, proliferative, and transforming functions. First, we have found that c-Myc-accelerated apoptosis does not directly correlate with its ability to transactivate transcription using the endogenous ornithine decarboxylase (ODC) gene as readout for transactivation. Furthermore, deletion of the conserved c-Myc box I domain implicated in transactivation does not inhibit apoptosis. Second, the ability of c-Myc to repress transcription, using the gadd45 gene as a readout, correlates with its ability to accelerate apoptosis. A conserved region of c-Myc implicated in mediating transrepression is absolutely required for c-Myc-accelerated apoptosis. Third, a lymphoma-derived Thr58Ala mutation diminishes c-Myc-accelerated apoptosis through a decreased ability to induce the release of cytochrome c from mitochondria. This mutation in a potential phosphorylation site does not affect cell cycle progression, providing genetic evidence that induction of cell cycle progression and acceleration of apoptosis are two separable functions of c-Myc. Finally, we show that the increased ability of Thr58Ala mutant to elicit cellular transformation correlates with its diminished ability to accelerate apoptosis. Bcl-2 overexpression blocked and the lymphoma-associated Thr58Ala mutation decreased c-Myc-accelerated apoptosis, and both led to a significant increase in the ability of Rat1a cells to form colonies in soft agar. This enhanced transformation was greater in soft agar containing a low concentration of serum, suggesting that protection from apoptosis is a mechanism contributing to the increased ability of these cells to proliferate in suspension. Thus, we show here for the first time that, in addition to mutations in complementary antiapoptotic genes, c-Myc itself can acquire mutations that potentiate neoplastic transformation by affecting apoptosis independently of cell cycle progression.

* Corresponding author. Mailing address: Department of Molecular Genetics, M/C 669, University of Illinois at Chicago, 900 South Ashland Ave., Chicago, IL 60607. Phone: (312) 355-1684. Fax: (312) 355-2032. E-mail: nhay{at}uic.edu.

dagger Present address: Department of Medicine, University of Chicago, Chicago, IL 60637.

Dagger Present address: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.

Molecular and Cellular Biology, August 2000, p. 6008-6018, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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