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)
Evan
G
G
Biochemistry of the Cell Nucleus Laboratory, Imperial Cancer Research Fund, London, U.K.
Harrington
E
E
Fanidi
A
A
Land
H
H
Amati
B
B
Bennett
M
M
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