The c-Myc protein, encoded by c-myc gene, in its wild-type form can induce tumors with a high frequency and can induce massive programmed cell death (PCD) in most transgenic mouse models, with greater efficiency than other oncogenes. Evidence also indicates that c-Myc can cause proliferative inhibition, i.e., mitoinhibition. The c-Myc-induced PCD and mitoinhibition, which may be attributable to its inhibition of cyclin D1 and induction of p53, may impose a pressure of compensatory proliferation, i.e., regeneration, onto the initiated cells (cancer progenitor cells) that occur sporadically and are resistant to the mitoinhibition. The initiated cells can thus proliferate robustly and progress to a malignancy. This hypothetical thinking, i.e., the concurrent PCD and mitoinhibition induced by c-Myc can promote carcinogenesis, predicts that an optimal balance is achieved between cell death and ensuing regeneration during oncogenic transformation by c-Myc, which can better promote carcinogenesis. In this perspective, we summarize accumulating evidence and challenge the current model that oncoprotein induces carcinogenesis by promoting cellular proliferation and/or inhibiting PCD. Inspired by c-myc oncogene, we surmise that many tumor-suppressive or growth-inhibitory genes may also be able to promote carcinogenesis in a similar way, i.e., by inducing PCD and/or mitoinhibition of normal cells to create a need for compensatory proliferation that drives a robust replication of initiating cells.
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pathway and/or induction of D1 to gain survival abilities. Most We wish to thank Dr. Fred Bogott at Austin Medical Center, studies on the oncogenicity of c-myc have so far focused on the Austin, MN, for his excellent English editing and valuable dis-lineage from a normal status to a malignancy whereas the inter-cussions. This work is supported by NIH grant RO1 CA100864 action between initiated cells and their surrounding normal cells to D.J.L.
- Compensatory proliferation
- Cyclin D1