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BackgroundThe MYC protein controls cellular functions such as differentiation, proliferation, and apoptosis. In response to genotoxic agents, cells overexpressing MYC undergo apoptosis. However, the MYC-regulated effectors acting upstream of the mitochondrial apoptotic pathway are still unknown.Principal FindingsIn this study, we demonstrate that expression of Myc is required to activate the Ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses in rat cell lines exposed to ionizing radiation (IR) or the bacterial cytolethal distending toxin (CDT). Phosphorylation of the ATM kinase and its downstream effectors, such as histone H2AX, were impaired in the myc null cell line HO15.19, compared to the myc positive TGR-1 and HOmyc3 cells. Nuclear foci formation of the Nijmegen Breakage Syndrome (Nbs) 1 protein, essential for efficient ATM activation, was also reduced in absence of myc. Knock down of the endogenous levels of MYC by siRNA in the human cell line HCT116 resulted in decreased ATM and CHK2 phosphorylation in response to irradiation. Conversely, cell death induced by UV irradiation, known to activate the ATR-dependent checkpoint, was similar in all the cell lines, independently of the myc status.ConclusionThese data demonstrate that MYC contributes to the activation of the ATM-dependent checkpoint responses, leading to cell death in response to specific genotoxic stimuli.

The c-Myc transcription factor is a key regulator of cell proliferation, differentiation, and apoptosis. While deregulation of myc induces programmed cell death, defects in the apoptotic program facilitate Myc-driven tumor development. We have treated c-Myc inducible mouse cells and rat fibroblasts with different c-myc status with cytotoxic drugs to explore the effect of c-Myc on drug-induced apoptosis. We found that c-Myc overexpression potentiated etoposide-, doxorubicin-, and cisplatin-induced cell death in mouse fibroblasts. In addition, these drugs provoked a strong apoptotic response in c-Myc-expressing cells, but a weak apoptosis in c-myc null Rat1 cells. In contrast, staurosporine-induced apoptosis was c-Myc-independent, confirming a functional apoptotic pathway in c-myc null cells. Apoptosis was paralleled by c-Myc-dependent Bax-activation after etoposide and doxorubicin treatment, but not after cisplatin administration. All three drugs induced higher caspase activation in c-Myc expressing cells than in c-myc null cells. Furthermore, etoposide treatment of c-Myc expressing cells resulted in PKCdelta cleavage, while inhibition of PKCdelta reduced etoposide-induced apoptosis and prevented Bax activation. Taken together, these findings suggest that Bax and caspase activation, together with PKCdelta signaling are involved in c-Myc-dependent etoposide-induced apoptosis.

Medulloblastoma and neuroblastoma are malignant embryonal childhood tumours of the central and peripheral nervous systems, respectively, which often show poor clinical prognosis due to resistance to current chemotherapy. Both these tumours have deficient apoptotic machineries adopted from their respective progenitor cells. This review focuses on the specific background for tumour development, and highlights biological pathways that present potential targets for novel therapeutic approaches.

The MYC oncogene is frequently deregulated in human tumors, indicative of a poor prognosis because of enhanced resistance to treatment. In such cases, the cellular sensitivity to chemotherapy could be restored by reactivation of Myc-driven apoptosis. We have analyzed apoptosis induced by the cytotoxic agents camptothecin (CPT) and paclitaxel (PTX) using Rat1 fibroblasts with different c-myc status and human Tet21N neuroblastoma cells with conditional MYCN expression. In these cell lines, the drug sensitivity was enhanced by Myc in line with previous reports showing that Myc sensitizes to apoptosis induction by many different apoptosis inducers. CPT-induced apoptosis involved cleavage and activation of proapoptotic Bid and Bax, induction of mitochondrial membrane depolarization, activation of caspase-9 and caspase-3, protein kinase c delta (PKCd) signaling and upregulation of p53. We also observed reduced transcriptional activity by Myc and other transcription factors in response to CPT. In contrast, the manner by which Myc potentiates the apoptosis induced by PTX differs from that of CPT and remains to be explored. In summary, our findings revealed that activation of PKCd in response to CPT treatment requires Myc and is important in CPT-mediated apoptosis signaling. ' 2007 Wiley-Liss, Inc.