[Cancer Research 65, 6485-6487, August 1, 2005]
© 2005 American Association for Cancer Research
Myc, Cell Competition, and Compensatory Proliferation
Peter Gallant
Zoologisches Institut, Universitaet Zurich, Zurich, Switzerland
Requests for reprints: Peter Gallant, Zoologisches Institut, Winterthurerstrasse 190, Universitaet Zurich, 8057 Zurich, Switzerland. Phone: 41-44-635-4812; Fax: 41-44-635-6820; E-mail: gallant{at}zool.unizh.ch.
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Abstract
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The proto-oncogene Myc is already known to affect many cellular processes, but recent experiments in the fruit fly Drosophila melanogaster have revealed yet a new facet of Myc. Neighboring cells were shown to compare their Myc levels and the losers (cells with lower Myc activity) were actively eliminated. This phenomenon is called "cell competition," and it seems to be part of a developmental size and quality control program. Subversion of this mechanism may contribute to the transforming powers of Myc and possibly other oncogenes.
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Background
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In recent years, the modest fruit fly Drosophila melanogaster has become a popular model system for the analysis of cellular growth control and organ size determination during animal development. For their studies, many biologists have focused on the so-called wing imaginal discs, the precursor organs of adult wings and thoraxes. Wing imaginal discs originate from a group of 40 to 50 cells that are set aside at the end of embryogenesis. During the 4 days of larval development, these cells multiply 1,000-fold to form the mature imaginal disc, which consists mainly of a columnar epithelial monolayer (1). The cellular growth and cell cycle characteristics during this proliferative phase closely resemble those of vertebrate cells, inasmuch as similar regulatory proteins have been found to function in both situations. In contrast to cells cultured on plastic, however, imaginal disc cells are embedded in an intact tissue and subject to physiologic short- and long-range signals that cannot be observed in vitro. One phenomenon based on such signals was identified 30 years ago: cell competition. Cell competition was observed with a group of mutations called Minutes (M; ref. 2). Minutes are mutations in ribosomal protein genes (3) that are characterized by recessive lethality and by a dominant growth defect. Thus, heterozygous M+/– flies are delayed in their development and take longer to reach their normal size, a reflection of the slower growth rate of M+/– cells. Importantly, however, M+/– cells are viable and can give rise to almost normal-looking animals. In striking contrast, when clones of slow-growing M+/– cells are generated in an animal that otherwise consists of wild-type cells, the M+/– cells are actively eliminated—a process dubbed "cell competition"; although such clones can be observed shortly after they have been induced, within 2 days no more surviving M+/– cells can be seen (2).
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Key Finding
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A very similar growth defect was recently found to be associated with the sole Drosophila orthologue of the proto-oncogene Myc, dMyc. Whereas dmyc is an essential gene, hypomorphic dmyc mutations are viable and only characterized by a modest growth defect. However, when clones of cells carrying such a hypomorphic dmyc mutation are surrounded by phenotypically wild-type cells, they suffer from the same type of cell competition as seen for M+/– cells (4). Interestingly, this cell competition is not simply caused by cellular defects associated with the dmyc mutation: Even wild-type cells were shown to be competed when they are surrounded by cells overexpressing dMyc, suggesting that cells somehow compare their dMyc level to that of their neighbors and it is this relative dMyc level that determines whether a cell is competed out of existence (5, 6); importantly, as little as 2-fold differences in dMyc levels are already sufficient to trigger cell competition. This dMyc-dependent cell competition shares two characteristics with the competition of M+/– cells by wild-type cells. First, both only act over a short distance—wild-type cells are only competed up to eight cell diameters from dMyc-overexpressing cells. Second, this cell competition does not function across the boundary between the anterior and the posterior compartment of the wing disc (roughly corresponding to two halves of the wing disc; i.e., wild-type cells in the posterior compartment are not competed by dMyc-overexpressing cells situated in the anterior compartment). The molecular basis for these features is not clear.
Similar types of cell competition have also been described for other genes, e.g. Ras and the Ste20-like kinase Slik (7–9). As Ras has been shown to control dMyc protein levels posttranscriptionally, its effects on cell competition might be mediated by dMyc; for Slik, the relevant downstream effectors are unknown. It is important to note, however, that not all mutants affecting growth induce cell competition and a simple difference in growth rate between neighboring cells is not sufficient to trigger competition. In particular, mutations in the insulin-signaling pathway, one of the main controllers of growth and organ size in Drosophila, strongly reduce growth but do not induce competition; conversely, overexpression of phosphoinositide-3-OH kinase (which acts downstream of the insulin receptor) entails massive overgrowth but does not lead to elimination of neighboring wild-type cells. Similarly, overexpression of cyclin D in combination with Cdk4 promotes cell-autonomous overgrowth without affecting adjacent cells (5). What then distinguishes dMyc from other growth promoters and places dMyc in the same category as Minutes? An explanation may be found in the molecular function of Myc. Myc is a transcription factor that controls the expression of a wide variety of target genes, but most notably components of the ribosome and proteins involved in ribosome assembly transcribed by RNA polymerase II (10–13), rRNAs transcribed by RNA polymerase I (14–16), and the products of RNA polymerase III (17). Myc deregulation, therefore, strongly influences the activity of ribosomes, and whatever mechanism is impaired in M+/– cells is likely to be also affected in dmyc mutants or upon dMyc overexpression. Consistent with this assumption, the Minute M(2)60E, which disrupts the ribosomal protein gene rpl19, a transcriptional target of dMyc, dominantly suppresses the ability of dMyc-overexpressing cells to compete their neighbors away (6).
There is currently no definitive explanation for how relative differences in ribosome activity could lead to cell competition. According to one scenario, a reduced efficiency in transducing the signal of the morphogen Decapentaplegic (Dpp, the principal transforming growth factor-ß family member in D. melanogaster) might play a role. It is not clear how impaired ribosome function might affect this process, but it has been shown that M+/– cells suffering from cell competition experience a lower Dpp response than their neighbors; both competed M+/– and dmyc mutant cells can be partially rescued by overstimulation of the endocytosis pathway that presumably also increases the efficiency of Dpp signal transduction. We do not know how the Dpp signaling activities are compared between neighboring cells, but a relative reduction of Dpp signal can then activate the stress-inducible Jnk pathway that ultimately triggers the execution of the apoptotic program (6, 18). The requirement for Jnk signaling for cell competition has been disputed, however, and it has been suggested that only the proapoptotic gene hid, but not jnk, is required for the induction of apoptosis (5). It should also be noted that cell competition has also been reported for cells with an inappropriately overactive Dpp pathway (19); furthermore, two other recent publications have shown that even cells completely lacking the ability to transduce the Dpp signal may be able to survive—although these cells are still forced to leave the epithelial monolayer and, thus, may experience at least some aspects of cell competition (20, 21).
Whatever the molecular mechanism of cell competition, it is generally assumed that this process provides a means of quality control whereby slowly proliferating (i.e., potentially damaged) cells are eliminated and replaced by their fitter neighbors. Cell competition also plays an important role in the regulation of organ size (5). When cell competition is reduced in the wing imaginal disc, by means of a mutation in the proapoptotic gene hid, the average size of adult wings is unchanged, but the distribution of wing sizes becomes much broader than in wild-type control (i.e., many more wings are either much smaller or much bigger than the average). Consistent with a role for cell competition in size control, overexpression of either phosphoinositide-3-OH kinase or cyclin D plus Cdk4 in a subset of cells in the wing imaginal disc result in an increased adult wing size; in contrast, dMyc overexpression in the same system only induces cell autonomous overgrowth, but thanks to cell competition the resulting adult wings have wild-type size. However, when ectopic dMyc expression is extended to all cells of the wing imaginal disc, no more cells with relatively lower dMyc levels are left that could be competed away, and as a result of the growth-promoting effects of dMyc the adult wings are significantly larger than wild type (5).
Thus far, we have discussed the story of dMyc and cell competition. A recent set of publications has now added an interesting twist to the interaction between slow- and fast-growing cells. These studies began with the observation that normal adult structures are developed from Drosophila imaginal discs, even if half of all cells in the imaginal disc are artificially eliminated (e.g., by X-irradiation; ref. 22). To find out how imaginal discs could cope with such a massive loss, three groups used different means to initiate apoptosis and then prevented the execution of downstream processes by ectopic expression of the viral protein p35 (which blocks downstream executor, but not the upstream initiator caspases; refs. 23–25). Whereas the publications disagree with respect to the relative importance of different triggers to induce apoptosis (diap1 inactivation versus Dronc activation), they all agree that the resulting "undead" cells then synthesize some growth factors, which stimulate proliferation of the surrounding wild-type cells. Ryoo et al. (25) go on to show that the generation of this stimulatory signal requires the activation of the Jnk pathway, and both Perez-Garijo et al. (23) and Ryoo et al. (25) identify the secreted growth factors as Wg and Dpp. How exactly these growth factors promote proliferation in the recipient cells was not analyzed any further, but it is conceivable that part of the effects of Dpp is mediated by dMyc, as Dpp has previously been reported to positively regulate dmyc expression in the wing imaginal disc (26).
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Meaning and Implication
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This brings us back to cell competition. Based on the data discussed above, the close collaboration of cell competition and compensatory proliferation is likely to be important for the proper development of different fly tissues (see Fig. 1 for a graphical summary of the data). At present, we can only speculate about the possible relevance of these processes for non-insects. It is an intriguing possibility, however, that mutations in genes involved in cell competition or compensatory proliferation might contribute to deregulated growth and cancer. Mutational activation of myc genes is certainly widely encountered in human tumors. Myc overexpression contributes in many ways to cellular transformation, but the ability of Myc-overexpressing cells to kill their normal neighbors (by means of cell competition) would certainly add to their selective advantage (6). On the other hand, Myc overexpression has long been known to induce apoptosis cell autonomously, and Myc-overexpressing cells need to acquire secondary mutations to avoid an untimely death (27). It is well conceivable that such an antiapoptotic mutation might lock a cell in a state similar to that of the "undead" wing imaginal disc cells overexpressing p35—and as a consequence such cells might permanently synthesize (self-stimulatory) growth factors (25).
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Figure 1. A speculative model for cell competition and compensatory proliferation. Ribosomal activity (i.e., the general ability of a cell to synthesize proteins) defines the "fitness" of a cell; this fitness is strongly influenced by Myc, because Myc plays a central role in controlling the levels of ribosomal components. Mutations in any component of the ribosome assembly line (e.g., in myc) reduce the fitness of a cell compared with its neighbor; this reduced fitness in turn impairs the ability of the mutant cell to transduce Dpp signals (by some unknown mechanism). Dpp signaling levels are (somehow) compared between neighboring cells; a cell autonomous reduction in Dpp signal transduction (compared with the neighbors) then triggers an apoptotic program through the activation of the Jnk pathway and/or the hid gene, which has two ultimate consequences: the elimination of the faulty cell and the emission of a Dpp or Wg signal to the neighborhood (which hereby is incited to replace the dying cell). The imminent death of the signal-sending cell ensures that this proproliferative signal is very short-lived and does not self-amplify, and, furthermore, that the overall distributions of the morphogens Wg and Dpp (which are important to shape the wing) are not grossly disturbed (25).
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None of these possible mechanisms have been experimentally examined. It should be noted, however, that recent experiments with murine embryonic stem cells carrying a mutation in the gene coding for the ribosomal protein RpL24 have revealed the existence of a phenomenon similar to cell competition in vertebrates (28). No doubt, we will soon hear more about the influence of cell competition and compensatory proliferation on vertebrate development and disease.
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Acknowledgments
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Grant support: Swiss National Science Foundation.
I thank K. Basler for critical reading of the manuscript.
Received 3/31/05.
Revised 5/22/05.
Accepted 5/31/05.
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References
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Abstract
Background
