PRINCIPLES OF TOXICOLOGY

The Rb gene encodes a 107-kD nuclear protein that plays a critical role in the early stage of the
cell cycle. When the cell is stimulated by a growth factor, that signal is ultimately relayed to the nucleus.
This signal results in the production of proteins that temporarily inactivate Rb. In its active form, the
Rb protein is tightly bound to an important transcription factor, E2F. When the cell receives a signal
to divide, Rb is hyperphosphorylated, causing a conformational change and the release of E2F. The
transcription factor E2F induces the production of other proteins involved in cell cycle progression.
The Cell Cycle and Apoptosis
13.4 MOLECULAR ASPECTS OF CARCINOGENESIS 285
It is important to discuss some of the processes that govern the life and death of cells to better understand
how oncogenes and tumor suppressor genes are involved in these processes. As pointed out previously,
proto-oncogenes function in various capacities in the transduction of signals for cell growth and
differentiation within and between cells. In normal cells, replication of the DNA and cell division is
stimulated by the presence of growth factors that bind receptors at the cytoplasmic membrane and
initiate a cascade of intracellular signals. Once these signals reach the nucleus they cause the
transcription of a complex array of genes, producing proteins that mediate progression of the cell
through the cell cycle culminating in mitosis or cell division.
The cell cycle is divided into five phases (Figure 13.6). The length of each of these phases can vary
depending on factors such as cell type and localized conditions within the tissue. After completing
mitosis (M), daughter cells enter the Gap 1 (G 1 ) phase. If conditions are favorable, cells enter the
synthesis (S) phase of the cycle, where the entire genome of the cell is replicated during DNA synthesis.
Following S phase, cells enter the Gap 2 (G 2 ) phase before proceeding through mitosis again. There
is a critical boundary early in G 1 called the restriction point. This is the point at which the cell must
Figure 13.6 Schematic diagram of the cell cycle including primary checkpoints.