Reviewing once more the c-myc and Ras collaboration

Abstract

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.

Acknowledgements

We would like to thank Dr. Fred Bogott at the Medical Center of Austin of Minnesota, for his excellent English editing of the manuscript. This work was supported by a NIH grant (RO1CA100864) to D.J. Liao.

Figures and Tables

Figure 1 Ras, which is usually induced by EGF and many other extracellular mitogenic stimuli, activates cycD1 to promote cell replication. However, Ras can also inhibit CDK4 and induce CDK inhibitors (p16, p21 and p27), which sometime causes growth arrest or apoptosis. On the contrary, c-myc can induce CDK4 and inhibit cycD1. Therefore, the c-myc and Ras collaboration may converge at the cycD1-CDK4. c-myc may also directly collaborate with cycD1 when cycD1 is induced by Ras or other growth stimuli. (Arrows and “⊤” indicate stimulation and inhibition, respectively).

Figure 2 Three mechanisms for the functions of cycD1: (1) cycD1 binds to CDK4 or CDK6 to form a holoenzyme that phosphorylates its substrates like Rb, BRCA1 and Smad. This is the canonical mechanism for cycD1's oncogenic role. (2) cycD1 binds CDK4, CDK6 or their kinase-dead mutants. These cycD1-CDK4/6 complexes cannot phosphorylate their substrates but can still bind CDK inhibitors such as p21 or p27, resulting in a sequestration of these inhibitors. As a consequence, other cyclin-CDK complexes such as cyclin E-CDK2 are less inhibited, i.e., more active. This kinase-irrelevant function of cycD1 may be oncogenic. (3) Instead of binding to CDK4 or CDK6, cycD1 can also form a complex with some transcriptional regulatory proteins to regulate transcription of genes. This CDK-irrelevant function may or may not be oncogenic, depending on the genes that are regulated.

Figure 3 Coordination of in vitro and in vivo concepts of tumor biology. Up-part: Spontaneous carcinogenesis in animals contains two steps, i.e., initiation and promotion. While immortalization of a cell in culture is equivalent to initiation, transformation may be equivalent to promotion if it includes additional properties (question markers) between colony formation in agar and xenograft tumor in mice and probably also beyond the xenograft tumor. Moreover, It is unclear (question markers) whether a benign tumor results from a clonal expansion of an initiated cell without undergoing promotion or without completion of a promotion stage. A benign status of a cell in culture should have been immortalized and should encompass additional properties towards malignancy that are currently unidentified. Moreover, some, but not all, benign cell lines may encompass a potential to progress to a malignant status, and measurable features of this potential (question marker) should be identified. Low-part: Different from the general situation described in the up-part, in certain animal models of spontaneous carcinogenesis, a cell that may have started but not yet completed an initiation process has already entered and completed the promotion process, thus manifested a malignant histology when the cell propagates to form a tumor. The tumor will regress upon withdrawal of the cancer inducer (sex steroids, chemical carcinogens or oncogenes), but a prolonged presence of the inducer will eventually facilitate the completion of the initiation, manifested as a sustained growth of a truly malignant tumor, even when the inducer is withdrawn. Similarly, in certain in vitro situations, the immortalizing process may not have been completed when the transforming process has been started and completed. The cell may thus develop to a malignant tumor when inoculated into an immunodeficient mouse, and the tumor cells may complete the immortalizing process in the host animal, manifested as a truly malignant xenograft tumor.