ReviewGrowth regulation by oncogenes — new insights from model organisms
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:
of special interest
of outstanding interest
References (82)
- et al.
Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein
Curr Biol
(1997) - et al.
Drosophila myc regulates cellular growth during development
Cell
(1999) - et al.
Ras1 promotes cellular growth in the Drosophila wing
Cell
(2000) - et al.
Control of cell growth by c-Myc in the absence of cell division
Curr Biol
(1999) - et al.
Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice
J Biol Chem
(1995) - et al.
Ras — a versatile cellular switch
Curr Opin Genet Dev
(1998) - et al.
Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4
Cell
(1999) - et al.
Regulation of imaginal disc cell size, cell number and organ size by Drosophila class I(A) phosphoinositide 3-kinase and its adaptor [published erratum appears in Curr Biol 1999 Nov 18;9(22):R867]
Curr Biol
(1999) - et al.
Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways
Dev Biol
(2000) - et al.
Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy
J Biol Chem
(2000)