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

Department of Stem Cell and Regenerative Medicine, and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 01/2011; 10(1):57-67. DOI: 10.4161/cc.10.1.14449
Source: PubMed


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.

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    • "Thus, it is possible that attenuation of c-Myc protein in RCC cells by PPARα antagonism was through increased let-7c resulting in decreased stability of c-Myc. The cyclin D1/CDK4 complex promotes cell cycle progression through phosphorylation of its substrate including pRb (reviewed in [42]). Attenuation of c-Myc represses cyclin D1/CDK4 expression and activity at G1/S transition [43], [44]. "
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    ABSTRACT: Renal cell carcinoma (RCC) is the sixth most common cancer in the US. While RCC is highly metastatic, there are few therapeutics options available for patients with metastatic RCC, and progression-free survival of patients even with the newest targeted therapeutics is only up to two years. Thus, novel therapeutic targets for this disease are desperately needed. Based on our previous metabolomics studies showing alteration of peroxisome proliferator-activated receptor α (PPARα) related events in both RCC patient and xenograft mice materials, this pathway was further examined in the current study in the setting of RCC. PPARα is a nuclear receptor protein that functions as a transcription factor for genes including those encoding enzymes involved in energy metabolism; while PPARα has been reported to regulate tumor growth in several cancers, it has not been evaluated in RCC. A specific PPARα antagonist, GW6471, induced both apoptosis and cell cycle arrest at G0/G1 in VHL(+) and VHL(-) RCC cell lines (786-O and Caki-1) associated with attenuation of the cell cycle regulatory proteins c-Myc, Cyclin D1, and CDK4; this data was confirmed as specific to PPARα antagonism by siRNA methods. Interestingly, when glycolysis was blocked by several methods, the cytotoxicity of GW6471 was synergistically increased, suggesting a switch to fatty acid oxidation from glycolysis and providing an entirely novel therapeutic approach for RCC.
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    • "The ability of CD47-null and thrombospondin-1-null cells to continuously proliferate could reflect either increased escape from senescence or induction of a self-renewing stem cell phenotype. Genes that enable primary cells to escape senescence and become immortalized include p53, Rb, p16-INK4A, and c-Myc28. Of these, only c-Myc mRNA levels were significantly elevated relative to HPRT1 mRNA levels in the primary cell cultures and remained elevated upon repeated passage (Fig. 1D, E). "
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    ABSTRACT: Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. c-Myc, Klf4, Oct4, and Sox2 expression is elevated in CD47-null endothelial cells, in several tissues of CD47- and thrombospondin-1-null mice, and in a human T cell line lacking CD47. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells and in vivo, whereas CD47 ligation by thrombospondin-1 suppresses c-Myc expression. The inhibitory effects of increasing CD47 levels can be overcome by maintaining c-Myc expression and are absent in cells with dysregulated c-Myc. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.
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    • "In these cells G1 progression is stimulated by growth factors, which trigger cell growth and activate the G1-S cell cycle machinery. The inhibition of Rbf, a member of the Drosophila Retinoblastoma family [22,49,50], results in release of E2F1 from the inhibitory complex with Rbf, which permits upregulation of E2F1 dependent S phase genes [51]. Imaginal disc cells maintain their size via the tight coupling of cell growth and cell cycle progression. "
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    ABSTRACT: Animal growth requires coordination of cell growth and cell cycle progression with developmental signaling. Loss of cell cycle control is extremely detrimental, with reduced cycles leading to impaired organ growth and excessive proliferation, potentially resulting in tissue overgrowth and driving tumour initiation. Due to the high level of conservation between the cell cycle machinery of Drosophila and humans, the appeal of the fly model continues to be the means with which we can use sophisticated genetics to provide novel insights into mammalian growth and cell cycle control. Over the last decade, there have been major additions to the genetic toolbox to study development in Drosophila. Here we discuss some of the approaches available to investigate the potent growth and cell cycle properties of the Drosophila counterparts of prominent cancer genes, with a focus on the c-Myc oncoprotein and the tumour suppressor protein FIR (Hfp in flies), which behaves as a transcriptional repressor of c-Myc.
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