Induction of Apoptosis by the c-Myc Helix-Loop-Helix/Leucine Zipper Domain in Mouse 3T3-L1 Fibroblasts

doi:10.1074/jbc.270.48.28797

Induction of Apoptosis by the c-Myc Helix-Loop-Helix/Leucine Zipper Domain in Mouse 3T3-L1 Fibroblasts *

From the (1)Institut für Klinische Molekularbiologie und Tumorgenetik, Forschungszentrum für Umwelt und Gesundheit, GSF, Marchioninistrasse 25, 81377 München, Federal Republic of Germany, the ICRF, Lincoln's Inn Fields, London WC2A 3PX, United Kingdom, and the
(2) Institut für Molekularbiologie und Biochemie, Freie Universität, Arnimallee 22, 14195 Berlin, Federal Republic of Germany

^¶ To whom correspondence should be addressed. Tel.: 49-89-7099512; Fax: 49-89-7099500.

Abstract

The cellular proto-oncogene c-myc is involved in cell proliferation and transformation but is also implicated in the induction of programmed cell death (apoptosis). The c-Myc protein is a transcriptional activator with a carboxyl-terminal basic region/helix-loop-helix (HLH)/leucine zipper (LZ) domain. It forms heterodimers with the HLH/LZ protein Max and transactivates gene expression after binding DNA E-box elements. We have studied the phenotype of dominant-negative mutants of c-Myc and Max in microinjection experiments. Max mutants with a deleted or mutated basic region inhibited DNA synthesis in serum-stimulated 3T3-L1 mouse fibroblasts. In contrast, mutants of c-Myc expressing only the basic region/HLH/LZ or HLH/LZ domains rapidly induced apoptosis at low and high serum levels. Co-expression of the HLH/LZ domains of c-Myc and Max failed to do so. We suggest that the c-Myc HLH/LZ domain induces apoptosis by specific interaction with cellular factors different to Max.

Footnotes

↵^§ A fellow of the Fonds der Chemischen Industrie.
↵* This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (SFB190) and Fonds der Chemischen Industrie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

BR

basic region

HLH

helix-loop-helix

LZ

leucine zipper

FCS

fetal calf serum

CMV

cytomegalovirus

NLS

nuclear localization signal

BrdUrd

5-bromo-2′-deoxyuridine

PBS

phosphate-buffered saline.
- Received July 13, 1995.
- Revision received September 15, 1995.