Review
Action of Myc in vivo — proliferation and apoptosis

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Abstract

The protein products of many dominant oncogenes are capable of inducing both cell proliferation and apoptosis. Recent experiments employing transgenic mice that express an ectopically regulatable myc gene or protein have begun to elucidate the role of the balance between proliferation and apoptosis in Myc-induced carcinogenesis. An outstanding feature of these experiments is the demonstration that the balance between oncogene-induced proliferation and apoptosis in a given tissue can be a critical determinant in the initiation and maintenance of the tumour.

Introduction

Myc is a potent inducer of both cell proliferation and apoptosis in vitro 1, 2, 3, 4, 5, 6, 7, 8•, 9•, 10. It is capable of preventing cells from exiting the cell cycle and of driving quiescent fibroblasts into continuous cycle 11, 12. Consistent with this, deregulated expression of Myc inhibits both differentiation and the concomitant growth arrest of some cell types. Recent evidence suggests that Myc sensitises cells to a variety of apoptotic triggers rather than directly inducing apoptosis by itself 9•, 13, 14••. Experiments in vitro suggest that the relative rates of proliferation and apoptosis induced by deregulated Myc and the presence of survival factors dictates the net outcome of the culture 13, 15. Sensitisaton to apoptotic stimuli is an intrinsic activity of Myc which, under normal cell culture conditions, is suppressed by a milieu of survival factors present in the calf serum used for in vitro culture [15]. Thus, Myc-induced apoptosis is usually only observed when such survival factors are withdrawn or cells express very high levels of Myc. Although some of the survival signalling pathways have been characterised in vitro, little is known about their role in vivo. It has been suggested that the ability of Myc to concomitantly induce proliferation and sensitise cells to apoptosis acts as a ‘fail-safe’ mechanism, guarding against a single proliferative lesion leading to unrestained cell growth 5, 8•. Thus, a cell that acquires deregulated Myc expression also exhibits an enhanced sensitivity to undergo apoptosis. In this scenario, survival of these cells depends on an adequate and continuous supply of survival factors or the acquisition of additional anti-apoptotic mutations. Analogous to the situation in vitro, it is likely that the net balance between Myc-induced proliferation and apoptosis determines the development of neoplasia (and ultimately the malignancy) potential of the transformed cell in vivo. Addressing the role of oncogenes in vivo, however, is somewhat limited given that the organism develops with the lesion already present, a situation that does not occur in sporadic tumour development in the adult. Ideally, one wishes to determine the immediate and short-term consequences of activating single oncogenes in adult tissues — a situation that most closely resembles the majority of tumours — rather than the combined effects of sustained oncogene activation during development and into the adult. Thus, an animal model in which one could regulate the activity of Myc was required. Moreover, the ability to turn off the oncogenic lesion at various stages of tumour development is essential in determining whether sustained Myc activation is required for tumour maintenance. This has recently been achieved and forms the basis of our review.

The c-myc proto-oncogene is intimately implicated in the control of cell proliferation and its deregulated expression is detected in many tumour cell types 16, 17. It has been assumed that such deregulated expression of Myc is instrumental in the initiation of the neoplastic phenotype. Most data, however, are derived from established tumours or cell lines bearing multiple oncogenic lesions. Given the ability of Myc to drive cell proliferation independently of the requirement for growth factors, it is possible that deregulated Myc expression is selected for during tumourigenesis and is, therefore, a rather late event. What, then, is the evidence that Myc is directly involved in neoplasia?

Several conventional transgenic studies employing tissue-specific expression of Myc proteins have attempted to address this question [18]. In these mouse models, the transgene is constitutively expressed in a particular tissue throughout the lifespan of the organism. Although much valuable information has emerged from such studies, interpretation of the resulting phenotypes is especially difficult with oncogenes such as myc that have concomitant and contradictory potentials to induce both cell proliferation and apoptosis. Tumours arising from sustained oncogenic activation often arise after relatively long latent periods and are usually clonal in origin suggesting that additional genetic lesions have contributed to the phenotype. Moreover, there is some evidence that deregulated Myc expression may itself contribute to increased genetic instability 19, 20, 21. Thus, the net observed phenotype seen in conventional Myc transgenics may be as a result predominantly of its mitogenic activity and Myc’s concomitant potential to induce apoptosis may well have been suppressed by mechanisms unknown during tumourigenesis. This is consistent with the observed oncogenic synergy between Myc and the anti-apoptotic protein Bcl-2 in lymphomagenesis 22, 23. Thus, the notion that Myc-induced apoptosis may act as a ‘fail-safe’ mechanism following activation of the oncogene cannot be addressed using constitutive expression of a myc transgene. These limitations have led to the development of transgenic mouse models in which the expression or activity of Myc is regulated ectopically 24, 25, 26••, 27••. Such studies have indicated that Myc is sufficient to initiate a benign neoplasia and to maintain a tumour in situ but the precise role of Myc in tumourigenesis is dependent on the tissue type and its environment (Table 1).

Section snippets

Ectopic Myc activation in skin causes proliferation with no detectable apoptosis

The epidermis is an ideal tissue in which to investigate the effects of Myc activation as the processes of proliferation, differentiation and cell death are tightly regulated and well understood; moreover, it is a major target of human neoplasia. Expression of the regulatable c-Myc protein, c-MycER (human c-Myc fused to the ligand-binding domain of a modified murine oestrogen receptor [12]), was targeted to suprabasal keratinocytes of the epidermis using the involucrin promoter [27••].

Myc activation causes pancreatic β cell apoptosis and diabetes

In striking contrast to skin, we find that the predominant effect of Myc activation in the β cells of the adult murine pancreas is apoptosis (S Pelengaris, unpublished data). Although Myc drives post-mitotic β cells into the cell cycle, sustained Myc activation leads to extensive β cell apoptosis resulting in involution of the pancreatic islets and diabetes within 7 days (Figure 1b). This suggests that, unlike Myc activation in the epidermis where apoptosis is suppressed, the early inhibition

The role of Myc-induced proliferation and apoptosis in lymphomas

Conventional transgenic animals have, in the past, been employed to demonstrate the involvement of Myc in lymphomagenesis. These models have been updated recently by the generation of a myc gene under the control of a tetracycline-responsive minimal promoter. Expression of this gene is regulated by the tetracycline-transactivating protein expressed under the control of the immunoglobulin heavy chain enhancer, Eμ [26••]. Lymphocytes from such transgenic animals express Myc in the absence but not

Conclusions

A major step towards the elucidation of the critical balance between Myc-induced proliferation and apoptosis in tumourigenesis has been facilitated by the development of ectopically regulatable oncogenes in transgenic mice. One, perhaps surprising, finding is that Myc alone is sufficient (at least in skin) to initiate and sustain the proliferative premalignant state. The reversibility of the T cell lymphomas observed by Felsher and Bishop [26••] indicates that Myc alone is also sufficient to

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

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