Reviewing once more the c-myc and Ras collaboration: Converging at the cyclin D1-CDK4 complex and challenging basic concepts of cancer biology

The c-myc is a proto-oncogene that manifests aberrant expression at high frequencies in most types of human cancer. C-myc gene amplifications are often observed in various cancers as well. Ample studies have also proved that c-myc has a potent oncogenicity, which can be further enhanced by collaborations with other oncogenes such as Bcl-2 and activated Ras. Studies on the collaborations of c-myc with Ras or other genes in oncogenicity have established several basic concepts and have disclosed their underlying mechanisms of tumor biology, including “immortalization” and “transformation”. In many cases, these collaborations may converge at the cyclin D1-CDK4 complex. In the meantime, however, many results from studies on the c-myc, Ras and cyclin D1-CDK4 also challenge these basic concepts of tumor biology and suggest to us that the immortalized status of cells should be emphasized. Stricter criteria and definitions for a malignantly transformed status and a benign status of cells in culture also need to be established to facilitate our study of the mechanisms for tumor formation and to better link up in vitro data with animal results and eventually with human cancer pathology.Key words: c-Myc, Cyclin D1, transformation, immortalization, oncogeneC-myc is the first proto-oncogene discovered and is known to participate in many cellular functions,¹ including maintenance of stem cell properties.² Most types of human cancer manifest aberrant expression of c-myc at high frequencies, and gene amplification occurs in many cases of various cancers as well. Ample studies have demonstrated that c-myc has a potent oncogenicity, which can be further enhanced by collaborations with other oncogenes such as a Ras mutant or with many extracellular growth stimuli that activate Ras, such as epidermal growth factor (EGF) or transforming growth factor α (TGFα). Studies on the collaborations of c-myc with Ras and other genes have provided us with mechanistic details behind several basic concepts of cancer biology, including the “two-hit principle”,³ “immortalization” and “transformation”. In the meantime, however, many results from these studies also challenge these basic concepts and thus confuse us. We now discuss the data on the collaborations of c-myc with Ras and other genes and present a perspective that these collaborations may converge at the cyclin D1-CDK4 complex. We also appeal to emphasize the importance of an immortalized status of cells and to establish stricter criteria to better define a transformed and benign statuses, so as to better connect in vitro results with animal data and with human cancer pathology.