Integrated control of cell proliferation and cell death by the c-myc oncogene.
Regulation of multicellular architecture involves a dynamic equilibrium between cell proliferation, differentiation with consequent growth arrest, and cell death. Apoptosis is one particular form of active cell death that is extremely rapid and characterized by auto-destruction of chromatin, cellular blebbing and condensation, and vesicularization of internal components. The c-myc proto-oncogene encodes an essential component of the cell's proliferative machinery and its deregulated expression is implicated in most neoplasms. Intriguingly, c-myc can also act as a potent inducer of apoptosis. Myc-induced apoptosis occurs only in cells deprived of growth factors or forcibly arrested with cytostatic drugs. Myc-induced apoptosis is dependent upon the level at which it is expressed and deletion mapping shows that regions of c-Myc required for apoptosis overlap with regions necessary for co-transformation, autoregulation, inhibition of differentiation, transcriptional activation and sequence-specific DNA binding. Moreover, induction of apoptosis by c-Myc requires association with c-Myc's heterologous partner, Max. All of this strongly implies that c-Myc drives apoptosis through a transcriptional mechanism: presumably by modulation of target genes. Two simple models can be invoked to explain the induction of apoptosis by c-Myc. One holds that death arises from a conflict in growth signals which is generated by the inappropriate or unscheduled expression of c-Myc under conditions that would normally promote growth arrest. In this 'Conflict' model, induction of apoptosis is not a normal function of c-Myc but a pathological manifestation of its deregulation. It thus has significance only for models of carcinogenic progression in which myc genes are invariably disrupted.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochemistry of the Cell Nucleus Laboratory, Imperial Cancer Research Fund, London, U.K.
G
G
Evan
E
E
Harrington
A
A
Fanidi
H
H
Land
B
B
Amati
M
M
Bennett
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D016207:Cytokines / Q000494:pharmacology; D005786:Gene Expression Regulation; D016259:Genes, myc; D006801:Humans; D000090063:Proto-Oncogene Mas
D016207:Cytokines; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas