The c-myc gene was discovered as the cellular homolog of the retroviral v-myc oncogene 20 years ago (23, 25, 167). The c-myc proto-oncogene was subsequently found to be activated in various animal and human tumors (37, 39, 42). It belongs to the family of myc genes that includes B-myc, L-myc, N-myc, and s-myc; however, only c-myc, L-myc, and N-myc have neoplastic potential (54, 82, 102, 118, 178). Targeted homozygous deletion of the murine c-myc gene results in embryonic lethality, suggesting that it is critical for development (43). Homozygous inactivation of c-myc in rat fibroblasts caused a marked prolongation of cell doubling time, further suggesting a central role for c-myc in regulating cell proliferation (121).

The frequency of genetic alterations of c-myc in human cancers (42) has allowed an estimation that approximately 70,000 U.S. cancer deaths per year are associated with changes in the c-myc gene or its expression. Given that c-myc may contribute to one-seventh of U.S. cancer deaths, recent efforts have been directed toward understanding the function of the c-Myc protein in cancer biology with the hope that therapeutic insights will emerge. Past efforts, which have contributed significantly to our current understanding of c-myc, are discussed in a number of excellent reviews (23, 29, 37, 40, 44, 52, 66, 82, 94, 102, 118, 125, 132, 145, 178, 182, 186).

https://mcb.asm.org/content/mcb/19/1/1.full.pdf

c-Myc target genes involved in cell growth, apoptosis, and metabolism

Deregulated expression of c-MYC occurs in a broad range of human cancers and is often associated with poor prognosis, indicating a key role for this oncogene in tumour progression. However, as established human tumours often bear multiple genetic lesions, it is difficult to determine whether c-MYC is instrumental in the initiation/progression of the tumour, or indeed whether inactivating c-MYC would lead to tumour regression. Regulatable transgenic mouse models of oncogenesis have shed light on these issues and provide hope for effective cancer therapies.

c-MYC: more than just a matter of life and death.

The activated product of the myc oncogene deregulates both cell growth and death check points and, in a permissive environment, rapidly accelerates the affected clone through the carcinogenic process. Advances in understanding the molecular mechanism of Myc action are highlighted in this review. With the revolutionary developments in molecular diagnostic technology, we have witnessed an unprecedented advance in detecting activated myc in its deregulated, oncogenic form in primary human cancers. These improvements provide new opportunities to appreciate the tumor subtypes harboring deregulated Myc expression, to identify the essential cooperating lesions, and to realize the therapeutic potential of targeting Myc. Knowledge of both the breadth and depth of the numerous biological activities controlled by Myc has also been an area of progress. Myc is a multifunctional protein that can regulate cell cycle, cell growth, differentiation, apoptosis, transformation, genomic instability, and angiogenesis. New insights into Myc's role in regulating these diverse activities are discussed. In addition, breakthroughs in understanding Myc as a regulator of gene transcription have revealed multiple mechanisms of Myc activation and repression of target genes. Moreover, the number of reported Myc regulated genes has expanded in the past few years, inspiring a need to focus on classifying and segregating bona fide targets. Finally, the identity of Myc-binding proteins has been difficult, yet has exploded in the past few years with a plethora of novel interactors. Their characterization and potential impact on Myc function are discussed. The rapidity and magnitude of recent progress in the Myc field strongly suggests that this marvelously complex molecule will soon be unmasked.

The myc oncogene: MarvelouslY Complex.

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 therapeutic utility in advanced malignancy, where c-Myc is frequently deregulated and where novel modalities are badly needed. Although its exact function remains obscure, c-Myc is a transcription factor and advances have been made in characterizing target genes which may mediate its apoptotic properties. Candidate regulators and effectors are also emerging. Among recent findings are connections to the CD95/Fas and TNF pathways and roles for the tumor suppressor p19ARF and the c-Myc-interacting adaptor protein Binl in mediating cell death. In this review I summarize the data establishing a role for 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 through separate 'death priming' and 'death triggering' mechanisms in which 'death priming' and mitogenic signals are coordinated. Investigation of the mechanisms that underlie the triggering steps may offer new therapeutic opportunities.

Mechanisms of apoptosis by c-Myc.

The proto-oncogene c-myc encodes a transcription factor c-Myc, which is of great importance in controlling cell growth and vitality. The quantity of c-Myc is carefully controlled by many mechanisms, and its actions to induce and repress genes are modulated by interactions with other regulatory proteins. Understanding the kinetic and quantitative relationships that determine how and what genes c-Myc regulates is essential to understanding how Myc is involved in apoptosis. Reduction of c-myc expression and its inappropriate expression can be associated with cellular apoptosis. This review outlines the nature and regulation of the c-myc gene and of c-Myc and presents the systems and conditions in which Myc-related apoptotic events occur. Hypotheses of the mechanisms by which expression and repression of c-myc lead to apoptosis are discussed.

The many roles of c-Myc in apoptosis

Publisher Summary This chapter reviews recent knowledge on the cell cycle regulation of c-Myc expression and c-Myc activity, as well as the structural features of the c-Myc protein that give new insights into the understanding of c-Myc function during the cell cycle and embryonic development. C-myc was the first nuclear proto-oncogene discovered and has been the subject of intense investigation during the past 16 years. The initial property attributed to c-Myc was its ability to transform normal cultured cells, but a great deal of evidence since then has indicated that this proto-oncogene is involved in a variety of different cellular processes—such as proliferation, differentiation, and apoptosis. The current focus of investigation into c-Myc is, therefore, primarily concerned with deciphering the way one gene can both participate in and discriminate between these seemingly divergent activities. Embryonic development requires cellular multiplication coupled to diversification of the genetic program, and therefore additional levels of control are required to provide a tight coordination between proliferation and differentiation. The biochemical analysis of c-Myc activity has been hampered by the extreme difficulty in obtaining a soluble form of the purified full-length protein. The chapter also discusses cell proliferation and c-Myc as a transcription factor. The majority of studies concerning c-Myc expression in adult tissues or embryos are related to the production of mRNA, although gene expression does not always strictly correlate with the temporal pattern and level of protein expression during development. While proliferating cells exhibit stable c-Myc RNA levels and abrupt changes in c-Myc expression are often observed during exit from the cell cycle, because cells undergo terminal differentiation. During the past decade it has become increasingly apparent that programmed cell death, or apoptosis, is a fundamental process affecting both growth and development.

c-Myc in the control of cell proliferation and embryonic development.

We report here unusual features of c-Myc specific to early embryonic development in Xenopus laevis, a period characterized by generalized transcriptional quiescence and rapid biphasic cell cycles. Two c-Myc protein forms, p61 and p64, are present in large amounts in the oocyte as well as during early development. In contrast, only p64 c-Myc is present in Xenopus somatic cells. p61 c-Myc is the direct translation product from both endogenous c-myc mRNAs and c-myc recombinant DNA. It is converted to the p64 c-Myc form after introduction into an egg extract, in the presence of phosphatase inhibitors. p61 and p64 belong to two distinct complexes localized in the cytoplasm of the oocyte. A 15S complex contains p64 c-Myc, and a 17.4S complex contains p61 c-Myc. Fertilization triggers the selective and total entry of only p64 c-Myc into the nucleus. This translocation occurs in a nonprogressive manner and is completed during the first cell cycles. This phenomenon results in an exceptionally high level of c-Myc in the nucleus, which returns to a somatic cell-like level only at the end of the blastulation period. During early development, when the entire embryonic genome is transcriptionally inactive, c-Myc does not exhibit a DNA binding activity with Max. Moreover, embryonic nuclei not only prevent the formation of c-Myc/Max complexes but also dissociate such preformed complexes. These peculiar aspects of c-Myc behavior suggest a function that could be linked to the rapid DNA replication cycles occurring during the early cell cycles rather than a function involving transcriptional activity.

Selective and rapid nuclear translocation of a c-Myc-containing complex after fertilization of Xenopus laevis eggs.

Core histone octamers reconstituted in vitro onto DNA fragments containing the chicken beta-globin gene promoter are precisely positioned with respect to the underlying DNA sequence [1]. Here we show that this is also true of the chicken beta-globin gene enhancer. These nucleosome binding sites are also employed within transfected COS cell nuclei, where the chicken beta-globin gene is transcriptionally inactive. Similar results were found in vivo, where positioned nucleosomes were detected over the inactive beta-globin promoter in chicken brain cells and 5-day red blood cells, and over the inactive beta-globin enhancer in brain cells. In contrast, the promoter and enhancer regions were found to be nucleosome-free in 15-day erythrocytes where the beta-globin gene is active. We argue that these results suggest a role for positioned nucleosomes in the regulation of the transcription of the chicken beta-globin gene.

The promoter and enhancer of the inactive chicken beta-globin gene contains precisely positioned nucleosomes.

Production of a functional full-length Xenopus laevis c-Myc protein in insect cells

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c-Myc in the control of cell proliferation and embryonic development.

Selective and rapid nuclear translocation of a c-Myc-containing complex after fertilization of Xenopus laevis eggs.

The promoter and enhancer of the inactive chicken beta-globin gene contains precisely positioned nucleosomes.

Production of a functional full-length Xenopus laevis c-Myc protein in insect cells