The Myc transcription factor network

Published on October 7, 2013   47 min
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My name is Bob Eisenman. I'm in the division of Basic Sciences at the Fred Hutchinson Cancer Research Center. In this lecture, I'm going to discuss the Myc transcription factor network. The Myc network is comprised of a group of highly conserved proteins known to play critical roles in the behavior of almost all normal cell types. In addition, these factors are deeply involved in the ideology of a wide range of human and other animal cancers. In what follows, I will draw on the work from many laboratories, including our own, in order to describe the components of the network, their interactions and activities, and what recent research is telling us about the manner in which they influence normal and abnormal cellular functions.
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The founding member of the Myc network and the jumping off point for this lecture is Myc itself. An important aspect of Myc is that transcription of the Myc gene and the subsequent production of its encoded Myc protein, is regulated by a large number of signal transduction pathways. Indeed, most major cytokines, growth factors and other mitogenic signals in many different cell types use signaling cascades that are known to stimulate gene transcription. A few of these are listed at the top of the slide. In many cases, induction of Myc transcription is an immediate early response to these signaling pathways. In other words, these pathways directly result in Myc transcription, and do not require any intervening protein synthesis to do so. In other cases, the induction of Myc occurs as an indirect response to signaling. The important point in either case, is that Myc gene represents a central node at which multiple mutagenic signals converge. It follows then, that the levels of Myc RNA and protein reflect the amount and duration of different signaling inputs. Studies from many labs have shown that in addition to its regulation by signal transduction pathways, the abundance of Myc RNA and protein is highly controlled at many other levels. These include transcriptional elongation, export of Myc RNA from the nucleus, stability of Myc RNA, translational control of Myc messenger RNA, and proteolysis of the Myc protein itself. It would seem that cells have evolved multiple mechanisms to keep tabs on the levels of Myc. We know that in most normal proliferating cells, as well as during normal embryonic development in many organisms, Myc is involved in critical aspects of cell behavior, including growth, metabolism, proliferation and the control of differentiation, and the apoptosis. Importantly, however, in situations where Myc expression is deregulated, and I will describe what I mean by this in a moment, there is evidence of increased growth in proliferation, altered metabolism, attenuated differentiation, increased apoptosis and genomic instability. All of these events are closely associated with the progression and maintenance of a tumor phenotype.
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The Myc transcription factor network

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