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A model depicting the modes of action of genotoxic and nongenotoxic carcinogens and the cooperation between proto-oncogenes and tumor suppressor
genes in transformation of normal cells with controlled proliferation into neoplastic cells with uncontrolled proliferation. When produced in appropriate
quantities, the normal proteins encoded by proto-oncogenes [1] and tumor suppressor genes [2] reciprocally influence mitosis and apoptosis and thus
ensure controlled cell proliferation. However, the balance between the effects of these 2 types of proteins on the fate of cells is offset by carcinogens via
genotoxic and nongenotoxic mechanisms resulting in uncontrolled proliferation.
A genotoxic Source:
(or DNA-reactive)
carcinogen
may
induceand
cellDoull's
proliferation
in 2 ways.
In theScience
first way,
inflicts DNA
Mechanisms
of Toxicity,
Casarett
Toxicology:
The Basic
of itPoisons,
8e damage (eg, by forming DNA adducts)
that ultimately brings about an activating mutation [3] in a proto-oncogene [1] and the mutant proto-oncogene (then called an oncogene) [4] in turn encodes
Citation: Klaassen CD. Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e; 2012 Available at: http://mhmedical.com/ Accessed:
a constitutively (ie, permanently) active oncogene protein [5] that continuously signals for mitosis or against apoptosis [6], depending on its function. In the
May 07, 2017
second way, the DNA-reactive chemical produces DNA damage that eventually yields an inactivating mutation [7] in a tumor suppressor gene [2], with the
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mutant gene [8] encoding an inactive tumor suppressor protein [9] that cannot restrain mitosis or evoke apoptosis (eg, in response to DNA damage). In
both instances, the rate of mitosis will exceed the rate of apoptosis [6] and uncontrolled proliferation of the affected cells will ensue [10]. Such a scenario