Jonas A Nilsson and John L Cleveland 1 Introduction

Myc oncogenes (c-Myc and its relatives N-Myc and L-Myc) are activated in a large cast of human cancers, as much as 70% of all malignancies. Thus, understanding how Myc contributes to tumor formation is a major focus of oncology research. The first Myc gene discovered was a viral oncogene, v-myc, the cancer-causing gene of the MC29 avian myelo-cytomatosis virus (1). Using v-myc as a probe, the cellular homolog MYC (c-Myc in mouse) was then identified (2,3), which turned out to be the very same gene translocated and juxtaposed to the immunoglobulin enhancers in human Burkitt lymphoma and in mouse plasmacytoma (4,5). Myc oncoproteins were subsequently found to be key regulators of the cell cycle (6-8) and the creation of their knockouts in mice revealed that c-Myc and N-Myc (but not L-Myc) are essential for mammalian development because c-Myc-and N-Myc-deficient embryos fail at mouse embryonic days E9.5 and E11.5, respectively 9-15). Analyses of these mice, and other cell-based studies, also established central roles for these oncoproteins as regulators of cell growth (i.e., cell mass) differentiation, cell adhesion, and vasculogenesis and angiogenesis (15-21) (Fig. 1).

Myc genes respond to extracellular mitogens as classical primary response genes and, conversely, Myc transcription is suppressed by signals that inhibit the growth of cells. Myc gene transcription is regulated by numerous signaling pathways known to be altered in cancer, including those directed by epidermal growth factor receptors, transforming growth factor-p, nuclear factor-KB, and Wnt and P-catenin (22,23). In addition, by mechanisms not fully understood, these signaling pathways, and others, can also stabilize myc transcripts, promote c-Myc translation, and alter the half-life of the protein (24). Finally, specific posttranslational modifications, including both phosphorylation and glycosylation (25-36), regulate the activity of these oncoproteins. Notably, virtually every level of control of these oncoproteins has been shown to be altered in cancer.

In cancer, Myc levels are elevated in response to amplification (e.g., MYCN and MYCL in neuroblastoma [6,8,37] and lung cancer [7], respectively), gene translocation

From: Polyamine Cell Signaling: Physiology Pharmacology and Cancer Research Edited by: J.-Y. Wang and R. A. Casero, Jr. © Humana Press Inc., Totowa, NJ

Extracellular Signals w

Differentiation

Fig. 1. Functions of Myc oncoproteins. Under physiological conditions, Myc contributes to the normal development of an organism by stimulating Myc target genes involved in cell proliferation, cell growth, cell division, and vasculogenesis and angiogenesis. When Myc is aberrantly expressed, as occurs in precancerous cells, apoptosis is triggered to protect cells from aberrant cell proliferation, that otherwise would lead to genomic instability that causes second hits that lead to overt malignancy (transformation).

Growth j Angiogenesis

Differentiation

Fig. 1. Functions of Myc oncoproteins. Under physiological conditions, Myc contributes to the normal development of an organism by stimulating Myc target genes involved in cell proliferation, cell growth, cell division, and vasculogenesis and angiogenesis. When Myc is aberrantly expressed, as occurs in precancerous cells, apoptosis is triggered to protect cells from aberrant cell proliferation, that otherwise would lead to genomic instability that causes second hits that lead to overt malignancy (transformation).

(e.g., MYC in B-cell malignancies [5]), enhanced transcription because of deregulation of proteins that regulate MYC transcription (e.g., in colon cancer in response to loss of Adenomatous polyposis coli [23]), or by mutations that lead to enhanced stability or altered activity of the protein (e.g., somatic MYC mutations in Burkitt lymphoma [26]). In turn, elevated levels of Myc results in an uncontrolled cell proliferation and, in malignancies, to the tumor angiogenic response (15,20,38,39). Given the vast array of events that can lead to Myc overexpression and that cancer is a rather rare incident in the life of an individual, it follows that cells possess intrinsic defense mechanisms that guard against elevated levels of Myc. Indeed, this checkpoint became evident when it was discovered that c-Myc (40,41) and other oncoproteins, such as E1A (42-44) and E2F-1 (45-48), are potent inducers of cell suicide (apoptosis) when overexpressed in normal cells (Fig. 1). Myc-induced apoptosis is particularly germane to the tumor cell, as it is especially evident under circumstances when cells are deprived of essential growth factors, or are exposed to DNA damage or hypoxia. The mechanisms responsible for Myc-induced apoptosis have recently been reviewed in depth elsewhere (49-51).

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