Can you have too much MYC?

Credit: CORBIS

The proto-oncogene MYC can activate tumour suppressor responses (ARF–p53, apoptosis or senescence) or proliferation, but what discriminates between these opposing biological outputs? Gerard Evan and colleagues now show that thresholds exist for the activation of each response, which has implications for the selective pressure that determines tumour progression.

MYC overexpression is usually restricted to advanced-stage tumours, whereas early lesions generally exhibit deregulated MYC expressed at relatively normal levels. To dissect the influence of constitutive (that is, deregulated) but relatively normal levels of MYC, Murphy, Junttila and colleagues generated transgenic mice in which the relatively weak Rosa26 promoter drives low-level expression of a Myc–oestrogen receptor (ER^T2) fusion gene (MycER^T2 or MER). The MER gene encodes a MYC protein (MYCER^T2) that is active in tissues only when tamoxifen is administered. R26^MER/WT and R26^MER/MER mice exhibited gene dosage-dependent expression of MycER^T2 (R26^MER/WT tissues express half that of R26^MER/MER mice). Activation of MYCER^T2 had no effect in R26^MER/WT mice but induced widespread proliferation in most tissues of R26^MER/MER animals, indicating that MYC expression must be above a specific threshold level to induce proliferation. However, even in R26^MER/MER mice, MYCER^T2 failed to induce either apoptosis or activation of the ARF–p53 tumour suppressor pathway in most tissues. The exception was colonic epithelium, which expressed higher protein levels of MYCER^T2 than other tissues. Markers of proliferation and apoptosis and ARF–p53 activation were evident, indicating that the threshold for activating tumour suppressor pathways is higher than that for proliferation. To confirm this, the authors used pIns–MycER^TAM mice that express ∼15-fold higher levels of MYCER^TAM in pancreatic β-cells than R26^MER/MER mice. In pIns–MycER^TAM, activation of high levels of MYC induced both proliferation and ARF expression, culminating in β-cell apoptosis and islet involution. By contrast, MYC activation in R26^MER/MER islets induced proliferation with no apoptosis, culminating in progressive islet hyperplasia. Similarly, sustained activation of low-level MYC in R26^MER/MER lung epithelium drove formation of hyperplastic and dysplastic epithelial foci, reminiscent of the early bronchioalveolar lesions that form in Kras^G12D transgenic mice. Indeed, crossing these two mouse models and activating MYC resulted in increased abundance and size of lung adenomas. This was not evident in R26^MER/WT; Kras^G12D mice.

These data indicate that deregulated, low-level oncogene activation may be characteristic of early-stage tumour development owing to the pressure to evade tumour suppressor responses. However, once selection pressure has resulted in the loss of key tumour suppressor pathways, oncogene activation may increase to advance tumour progression.