Mechanisms of apoptosis by c-Myc

Much recent research on c-Myc has focused on how it drives apoptosis. c-Myc is widely known as a crucial regulator of cell proliferation in normal and neoplastic cells, but until relatively recently its apoptotic properties, which appear to be intrinsic, were not fully appreciated. Its death-dealing aspects have gained wide attention in part because of their potential ther apeutic utility in advanced malignancy, where c-Myc is frequently deregulat ed and where novel modalities are badly needed. Although its exact function remains obscure, c-Myc is a transcription factor and advances have been ma de in characterizing target genes which may mediate its apoptotic propertie s. Candidate regulators and effecters are also emerging. Among recent findi ngs are connections to the CD95/Fas and TNF pathways and roles for the tumo r suppressor p19ARF and the c-Myc-interacting adaptor protein Bin1 in media ting cell death. In this review I summarize the data establishing a role fo r c-Myc in apoptosis in diverse settings and present a modified dual signal model for c-Myc function. It is proposed that c-Myc induces apoptosis thro ugh separate 'death priming' and 'death triggering' mechanisms in which 'de ath priming' and mitogenic signals are coordinated. Investigation of the me chanisms that underlie the triggering steps may offer new therapeutic oppor tunities.