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Myc regulates to some degree every major process in the cell. Proliferation, growth, differentiation, apoptosis, and metabolism are all under Myc control. In turn, these processes feed back to adjust the level of expression. Although Myc is regulated at every level from RNA synthesis to protein degradation, transcription is particularly responsive to multiple diverse physiological and pathological signals. These signals are delivered to the promoter by a wide variety of transcription factors and chromatin remodeling complexes. How these diverse and sometimes disparate signals are processed to manage the output of the promoter involves chromatin, recruitment of the transcription machinery, post-initiation transcriptional regulation, and mechanisms to provide dynamic feedback. Understanding these mechanisms promises to add new dimensions to models of transcriptional control and to reveal new strategies to manipulate Myc levels.

The Myc transcription factor functions as a downstream effector of most mitogenic signals. Myc is synthesized rapidly in response to extracellular mitogenic signals, and blocking Myc induction abolishes or at least severely attenuates any mitogenic response. Furthermore, ectopic Myc expression can often bypass the requirement for extracellular signals for entry into S phase. Thus, the Myc transcription factor is both necessary and in many ways sufficient to promote the growth of diverse cell types. Given this potent biological activity, it is not surprising that mutations in the gene are among the most frequent in human and animal cancers. Understanding the molecular basis of Myc function has been a central issue in the fields of cancer biology and signal transduction for 20 years.

Myc proteins are nuclear proteins that exert their biological functions at least in part through the transcriptional regulation of large sets of target genes. Recent microarray analyses show that several percent of all genes may be directly regulated by Myc. A large body of data shows that Myc proteins both positively and negatively affect transcription. The basic mechanism underlying Myc’s activation of transcription is well understood, but the mechanisms through which Myc negatively regulates or represses transcription are far less understood. In this chapter, we will review our current knowledge about this less-well-understood topic.

A significant body of evidence has been accumulated that demonstrates decisive roles of members of the Myc/Max/Mad network in the control of various aspects of cell behavior, including proliferation, differentiation, and apoptosis. The components of this network serve as transcriptional regulators. Mad family members, including Mad1, Mxi1, Mad3, Mad4, Mnt, and Mga, function in part as antagonists of Myc oncoproteins. At the molecular level this antagonism is reflected by the different cofactor/chromatin remodeling complexes that are recruited by Myc and Mad family members. One important function of the latter is their ability to repress gene transcription. In this review we summarize the current view of how this repression is achieved and what the consequences of Mad action are for cell behavior. In addition, we point out some of the many aspects that have not been clarified and thus leave us with a rather incomplete picture of the functions, both molecular and at the cellular level, of Mad family members.

Recently determined structures of a number of Myc family proteins have provided significant insights into themolecular nature of complex assembly and DNA binding. These structures illuminate the details of specific interactions that govern the assembly of nucleoprotein complexes and, in doing so, raisemore questions regarding Myc biology. In this review, we focus on the lessons provided by these structures toward understanding (1) interactions that govern transcriptional repression by Mad via the Sin3 pathway, (2) homodimerization of Max, (3) heterodimerization of Myc-Max and Mad-Max, and (4) DNA recognition by each of the Max-Max, Myc-Max, and Mad-Max dimers.

The c-Myc oncogenic transcription factor plays a central role in many human cancers through the regulation of gene expression. Although the molecular mechanisms by which c-Myc and its obligate partner, Max, regulate gene expression are becoming better defined, genes or transcriptomes that c-Myc regulate are just emerging from a variety of different experimental approaches. Studies of individual c-Myc target genes and their functional implications are now complemented by large surveys of c-Myc target genes through the use of subtraction cloning, DNA microarray analysis, serial analysis of gene expression (SAGE), chromatin immunoprecipitation, and genome marking methods. To fully appreciate the differences between physiological c-Myc function in normal cells and deregulated c-Myc function in tumors, the challenge now is to determine how the authenticated transcriptomes effect the various phenotypes induced by c-Myc and to define how c-Myc transcriptomes are altered by the Mad family of proteins.

The c-myc oncogene acts as a pluripotent modulator of transcription during normal cell growth and proliferation. Deregulated c-myc activity in cancer can lead to excessive activation of its downstream pathways, and may also stimulate changes in gene expression and cellular signaling that are not observed under non-pathological conditions. Under certain conditions, aberrant c-myc activity is associated with the appearance of DNA damage-associated markers and karyotypic abnormalities. In this chapter, we discuss mechanisms by which c-myc may be directly or indirectly associated with the induction of genomic instability. The degree to which c-myc-induced genomic instability influences the initiation or progression of cancer is likely to depend on other factors, which are discussed herein.

The past two decades of gene targeting experiments have allowed us to make significant strides towards understanding how the Myc/Max/Mad network influences multiple aspects of cellular behavior during development. Here we summarize the findings obtained from the knockout mice generated to date, namely those in which the N-, c-, L-, , , , , or genes have been targeted. A compilation of lessons we have learned from these knockout mouse models, and suggestions as to where future efforts could be focused, are also presented.

The Myc proto-oncogenes, their binding partner Max and their antagonists from the Mad family of transcriptional repressors have been extensively analysed in vertebrates. However, members of this network are found in all animals examined so far. Several recent studies have addressed the physiological function of these proteins in invertebrate model organisms, in particular . This review describes the structure of invertebrate Myc/Max/Mad genes and it discusses their regulation and physiological functions, with special emphasis on their essential role in the control of cellular growth and proliferation.

Recent experiments suggest the existence of a transcriptional network that functions in parallel to the canonical Myc/Max/Mad transcriptional network. Unlike the Myc/Max/Mad network, our understanding of this network is still in its infancy. At the center of this network is a Max-like protein called Mlx; hence we have called this network the Mlx network. Like Max, Mlx interacts with transcriptional repressors and transcriptional activators, namely the Mad family and the Mondo family, respectively. Similar to Max-containing heterodimers, Mlx-containing heterodimers recognize CACGTG E-box elements, suggesting that the transcriptional targets of these two networks may overlap. Supporting this hypothesis, we have observed genetic interactions between the orthologs of Myc and Mondo. In higher eukaryotes, two proteins, MondoA and MondoB/CHREBP/WBSCR14, constitute the Mondo family. At present little is known about the transcriptional targets of MondoA; however, pyruvate kinase is a putative target of MondoB/CHREBP/WBSCR14, suggesting a function for the Mondo family in glucose and/or lipid metabolism. Finally, unlike the predominant nuclear localization of Myc family proteins, both Mondo family members localize to the cytoplasm. Therefore, while the Myc and Mondo families may share some biological functions, it is likely each family is under distinct regulatory control.