Review
Growth regulation by oncogenes — new insights from model organisms

https://doi.org/10.1016/S0959-437X(00)00151-9Get rights and content

Abstract

A great deal of work has focused on how oncogenes regulate the cell cycle during normal development and in cancer, yet their roles in regulating cell growth have been largely unexplored. Recent work in several model organisms has demonstrated that homologs of several oncogenes regulate cell growth and has suggested that some of the effects of oncogenes on the cell cycle may be a result of growth promotion. These studies have also suggested how growth and cell-cycle progression may be coupled.

Introduction

Cancer results from the subversion of diverse cellular and organismal controls by ‘rogue’ genes, termed oncogenes. These are frequently the same genes that regulate normal cell functions — including growth, apoptosis, fate specification, adhesion, and cell-cycle control. Many studies of how oncogenes cause hyperproliferation have focused on their roles in regulating the cell cycle, even though both cell growth (i.e. increases in cell mass) and cell-cycle progression are required for the clonal expansion of transformed cells as they form a tumor. A recent flurry of papers looking at oncogenes in model organisms, however, has re-emphasized their roles in growth control. Model organisms offer the advantage of allowing investigation of how the homologs of oncogenes function in vivo by studying gain- and loss-of-function mutations using sophisticated transgene expression and mosaic analysis techniques. In this review, we discuss studies suggesting that the primary function of several oncogenes is to regulate cell growth (Fig. 1), explore the relationship between growth and cell-cycle regulators (Fig. 2), and highlight some unresolved issues.

Section snippets

Ras and Myc

Mutational activation of the Ras GTPase and overexpression of the Myc transcription factor play roles in the development of a wide range of tumors. Both are thought to link extracellular mitogenic signals to intracellular mechanisms that control cell proliferation, most notably by regulating progression through the G1/S transition of the cell cycle. A prominent model derived from work in cell culture suggests that Ras drives G1/S progression by inactivating the retinoblastoma (Rb) tumor

Mechanisms of growth regulation

With the knowledge that several oncogenes regulate growth, it is important to consider how they interact and what mechanisms they use. Experiments in both mammalian cell culture and Drosophila have demonstrated that expression of activated Ras increases protein levels of the Myc transcription factor, and work in Drosophila has suggested that dMyc at least partially mediates dRas1-driven growth [6, [49]. Myc targets, in turn, include regulators of the cell cycle, such as the G1/S regulators Cdk4

Regulation of growth during development

To appreciate how growth-regulatory pathways interact, it is also important to understand how they are utilized during normal development. A simple model predicts that proteins that pattern and specify cell fates in developing tissues, such as members of the Wnt/Wingless, Hedgehog, Notch, bone morphogenetic protein/Decapentaplegic and epidermal growth factor/Ras pathways, will also regulate cell growth and proliferation. These pathways do, in fact, regulate growth of developing tissues in a

Effects of growth on the cell cycle

Studies of oncogenes in model organisms have also yielded new insights on how growth is coupled to the cell cycle. Previous work in yeast and flies suggested that rates of cell growth dictate rates of cell proliferation [31], [67], [68]. This model is supported by the ability of overexpressed Drosophila CycD/Cdk4 or Arabidopsis CycD to coordinately increase rates of both cell growth and cell proliferation [43, [46. In contrast, overexpression of activated dRas1, dMyc, or dPI3K in the fly wing

Can cell-cycle regulators act as oncogenes?

We have focused thus far on the ability of oncogenes to promote growth but cell-cycle regulators can also be involved in tumor development. For example, overexpression of the cell-cycle regulators E2F, CycE, or Cdc25B in mice causes hyperplastic phenotypes in some cases [71], [72], [73], [74], [75], [76]. These mice can also develop tumors after long latencies, and are often predisposed to form tumors in combination with carcinogens or other oncogenes. However, the oncogenic properties of

Conclusions

Studies of oncogenes in model organisms have re-emphasized the roles of these genes in growth regulation and have suggested that some of their effects on the cell cycle may be consequences of growth promotion. It must now be determined whether the growth-promoting properties of oncogenes are conserved in humans and, if so, how common this property is. In fact, correlations between expression of growth-promoting oncogenes and cell size have been observed in humans [79], suggesting that some

Update

Similar to findings in B-lymphocytes [7, [8, Kim et al. [82] report that ectopic expression of Myc in mouse hepatocytes in vivo increases cell size with little effect on rates of cell proliferation or death. This is accompanied by enlarged nuclei and nucleoli and upregulated expression of ribosomal and nucleolar genes, consistent with Myc driving cell growth by inducing expression of components of the protein synthesis machinery.

Acknowledgements

We thank Ed Giniger, Sally Leevers, Piotr Sicinski, and George Thomas for helpful discussions and comments on the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • radical dotof special interest

  • radical dotradical dotof outstanding interest

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