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Human Gene Control by Vital Oncogenes: Revisiting a Theoretical Model and Its Implications for Targeted Cancer Therapy
Department of Medical Oncology, Cancer Treatment Centers of America, Eastern Regional Medical Center, 1331 Wyoming Ave, Philadelphia, PA 19124, USA
Received: 28 October 2011; in revised form: 18 December 2011 / Accepted: 20 December 2011 / Published: 27 December 2011
Abstract: An important assumption of our current understanding of the mechanisms of carcinogenesis has been the belief that clarification of the cancer process would inevitably reveal some of the crucial mechanisms of normal human gene regulation. Since the momentous work of Bishop and Varmus, both the molecular and the biochemical processes underlying the events in the development of cancer have become increasingly clear. The identification of cellular signaling pathways and the role of protein kinases in the events leading to gene activation have been critical to our understanding not only of normal cellular gene control mechanisms, but also have clarified some of the important molecular and biochemical events occurring within a cancer cell. We now know that oncogenes are dysfunctional proto-oncogenes and that dysfunctional tumor suppressor genes contribute to the cancer process. Furthermore, Weinstein and others have hypothesized the phenomenon of oncogene addiction as a distinct characteristic of the malignant cell. It can be assumed that cancer cells, indeed, become dependent on such vital oncogenes. The products of these vital oncogenes, such as c-myc, may well be the Achilles heel by which targeted molecular therapy may lead to truly personalized cancer therapy. The remaining problem is the need to introduce relevant molecular diagnostic tests such as genome microarray analysis and proteomic methods, especially protein kinase identification arrays, for each individual patient. Genome wide association studies on cancers with gene analysis of single nucleotide and other mutations in functional proto-oncogenes will, hopefully, identify dysfunctional proto-oncogenes and allow the development of more specific targeted drugs directed against the protein products of these vital oncogenes. In 1984 Willis proposed a molecular and biochemical model for eukaryotic gene regulation suggesting how proto-oncogenes might function within the normal cell. That model predicted the existence of vital oncogenes and can now be used to hypothesize the biochemical and molecular mechanisms that drive the processes leading to disruption of the gene regulatory machinery, resulting in the transformation of normal cells into cancer.
Keywords: oncogenes; gene regulation; gene transcription; transcription activator; targeted cancer therapy; signal transduction; carcinogenesis; protein kinase; cell cycle control; steroid hormone action
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Willis, R.E. Human Gene Control by Vital Oncogenes: Revisiting a Theoretical Model and Its Implications for Targeted Cancer Therapy. Int. J. Mol. Sci. 2012, 13, 316-335.
Willis RE. Human Gene Control by Vital Oncogenes: Revisiting a Theoretical Model and Its Implications for Targeted Cancer Therapy. International Journal of Molecular Sciences. 2012; 13(1):316-335.
Willis, Rudolph E. 2012. "Human Gene Control by Vital Oncogenes: Revisiting a Theoretical Model and Its Implications for Targeted Cancer Therapy." Int. J. Mol. Sci. 13, no. 1: 316-335.