Abstract
The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.
Highlights
The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions
Questions that date back to the initial discoveries remain at least partially unanswered: Which of the neoplasia-derived changes are decisive for its development and metastasis? Does a more frequent change mean it is more important? What network of oncogenic pathways is an essential setup for the initiation and driving of neoplasia at a given stage? We elaborate on these questions by focusing on the properties of individual oncogenes but rather by discussing the most representative examples of molecular interplay between universal and frequently studied oncogenic drivers
Even gene, which is known asCMYC-driven a powerful and indispensable of p53 interacts with the NFY family of transcription factors and allows p300 acetyltransferase to be both classic and modern multistep carcinogenesis models [4,5], is dependent on particular partners recruited to NFY gene promoters [30,31], which may involve recruitment of Yes-associated protein (YAP) transcription and molecular events to be effective in de novo cell transformation [6,7]
Summary
Since the discovery of the first cellular oncogenes in 1970s the idea that certain genes may promote cancer more efficiently than others has been sustained. P53 interactions with other oncogenic proteins are critical to executing the GOF mutated gene in human neoplasias (42–43% mutations [1,3]) with well-established tumor-suppressive activity. The main involvement mutant p53 in gain-of-function (Figure 1) It is a unique a tumor suppressor possible and a proto-oncogene intercepting properties other oncogenic pathways is viasetup its of specific interactions, due to “in one”, which remains somewhat controversial despite of studies covering thedomain. Even gene, which is known asCMYC-driven a powerful and indispensable of p53 interacts with the NFY family of transcription factors and allows p300 acetyltransferase to be both classic and modern multistep carcinogenesis models [4,5], is dependent on particular partners recruited to NFY gene promoters [30,31], which may involve recruitment of YAP transcription and molecular events to be effective in de novo cell transformation [6,7]. Paragraphs below), with more examples reviewed elsewhere [16,42]
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